KR20130131531A - Composition for enhancing sensitivity to anti-cancer agent comprising of suppressor of morphogenesis in genitalia-1 - Google Patents

Abstract

The present invention relates to a composition for enhancing sensitivity of an anti-cancer agent and, more particularly, to a composition comprising SMG-1 as an active ingredient for enhancing sensitivity of an anti-cancer agent; an anti-cancer composition including sorafenib and SMG-1 as active ingredients; and an anti-cancer composition comprising an expression vector including a polynucleotide encoding SMG-1 as an active ingredient. Suppressor of morphogenesis in genitalia-1 (SMG-1) according to the present invention has a function related to enhancing sensitivity of sorafenib on cancer cells. Therefore, when the resistance of sorafenib on cancer cell is controlled, SMG-1 helps suppression of growth of cancer cells and induction of apoptosis only using low concentration sorafenib, thereby enabling efficient cancer therapy.

Description

TECHNICAL FIELD The present invention relates to a composition for enhancing sensitivity of an anti-cancer agent containing SMG-1 as an active ingredient,

The present invention relates to a composition for enhancing the sensitivity of an anticancer agent, and more particularly, to a composition for promoting sensitivity to an anticancer agent comprising SMG-1 as an active ingredient; An anticancer composition comprising sorafenib and SMG-1 as an active ingredient; And an expression vector comprising a polynucleotide encoding SMG-1 as an active ingredient.

Cancer is one of the most deadly threats to human health. In the United States alone, there are 1.3 million new cancer patients each year, the second leading cause of death after cardiovascular disease, and it is estimated that approximately one in four deaths is a cancer patient. Most of these deaths are due to solid tumors. Although there has been considerable progress in the medical treatment of certain cancers, the overall 5-year survival rate for all cancers has improved by only about 10% over the past 20 years. Cancer, or malignant tumors rapidly metastasize and grow in an uncontrolled manner, it is extremely difficult to detect and treat them on time.

Currently, surgery, radiation therapy, and chemotherapy are used to treat cancer. Among them, chemotherapy is a method of treating cancer by using an anticancer agent, and it was used in earnest by obtaining a cure effect by using methotrexate for choriocarcinoma. Today, about 60 kinds of various anticancer drugs are used. Recently, as knowledge of cancer development and characteristics of cancer cells is well known, researches on the development of new anticancer drugs are being actively carried out.

Hepatocellular carcinoma (HCC) is an aggressive malignant tumor that has a poor prognosis and has a very complicated molecular process, which is not successful with conventional chemotherapy. Liver cancer is the fifth most common tumor in the world, with 500,000 deaths annually (Okuda 2000). The survival rate of patients with liver cancer has not improved over the past 20 years, and has almost the same incidence as the mortality rate (Marrero, Fontana et al. 2005). Exposure to carcinogens such as chronic hepatitis B and aflatoxin B1, which are caused by hepatitis B virus or hepatitis C virus infection, is known to be a major risk factor for liver cancer (Thorgeirsson and Grisham 2002).

To date, anticancer drugs on the market include nitrogene mustard, imatinib, oxaliplatin, rituximab, elotinib, neratib, lapatinib, zetitib, vandetanib, nilotinib, semathanib, But are not limited to, nisin, cediranib, lestaurintinib, trastuzumab, gepetinib, bortezomib, sunitinib, carboflatin, sorafenib, bevacizumab, cisplatin, cetuximab, bismuth alum, asparaginase, tretinoin , Hydroxycarbamides, dasatinib, estramermin, gemtuzumab ozogamicin, ibritumomatocetane, heptaplatin, methylaminoburenic acid, amsacrine, alemtuzumab, procarbazine, Dithiothreitol, diltiazem, holmium nitrate, chitosan nitrate, gemcitabine, doxifluridine, femetrexed, tegafur, capecitabine, gimeracin, atheracil, azacytidine, methotrexate, uracil, cytarabine, fluorouracil, Vin, Enoshita , Vinblastine, vinblastine, vinblastine, vinblastine, vinblastine, topotecan, vinorelbine, etoposide, vincristine, vinblastine, paclitaxel, docetaxel, decitabine, mercaptopurine, thioguanine, cladribine, But are not limited to, antibiotics, antioxidants, antioxidants, antioxidants, antioxidants, antioxidants, antioxidants, antioxidants, antioxidants, antioxidants, antioxidants, antioxidants, But are not limited to, mousse, temozolomide, patches, ifosfamide, cyclophosphamide, melphalan, altretamine, dacarbazine, thiotepa, nimustine, chlorambucil, mitolactol, But are not limited to, those selected from the group consisting of stannous, aminoglutethimide, anagrelide, navelin, pradrazol, tamoxifen, toremifene, testolactone, anastrozole, letrozole, borozol, bicalutamide, There are various kinds.

In particular, sorafenib is a promising candidate for overexpression of the receptor tyrosine kinase VEGFR-2, platelet-derived growth factor receptor (PDGFR) -β, c-kit, Is known to be an oral anticancer drug that simultaneously inhibits the serine / threonine kinase (Raf kinase) pathway of serine / threonine kinase. This is a clinical trial of various solid tumors, which are already being used as anticancer drugs in renal cell carcinoma, and clinical studies on hepatocellular carcinoma (HCC) have been conducted recently, and the US Food and Drug Administration It was approved as a treatment for liver cancer.

However, the therapeutic effect of sorafenib hepatocellular carcinoma (HCC) is not significant, and it only shows minimal survival and minimal progress of liver cancer in patients with advanced hepatocellular carcinoma. The lowering of the therapeutic efficacy of such a treatment with sorapenib is due to the anticancer drug resistance (non-reactivity or resistance).

In order for cancer chemotherapy to be successful, patients should be able to tolerate adverse effects at the blood concentration at which normal tissues can survive, and cancer cells Drug resistance to an anti-cancer drug refers to a case in which cancer cells do not die despite administration of an anti-cancer drug that can reach a concentration capable of killing the cancer cells. Anticancer drug resistance may vary from patient to patient and may even be caused by a variety of factors including genetic differences between tumors derived from the same tissue.

As described above, one of the conventional methods for treating cancer has been chemotherapeutic administration, but many problems remain in determining the proper concentration for cancer cell death and normal cell survival. In order to treat cancer cells more effectively, administration of a high concentration of an anticancer agent may induce apoptosis to normal cells. Therefore, it is necessary to develop a method of inhibiting the growth of cancer cells or inducing their death by administering a low concentration of an anticancer drug.

Korean Patent Laid-Open No. 10-2011-0028854 discloses an inhibitor of cancer cell growth and an agent for enhancing anticancer drug sensitivity through regulation of CANu1, a protein associated with colorectal cancer. However, until now, to be.

Therefore, the present inventors performed genetic screening using RNAi to identify genes associated with anticancer drug resistance (non-reactivity or resistance), and found that SMG-1 (Suppressor of Morphogenesis in Genitalia-1) Or resistance, and thus completed the present invention.

Korean Patent Publication No. 10-2011-0028854

Therefore, an object of the present invention is to provide a novel use of SMG-1 as an agent for improving the sensitivity of an anticancer agent.

Another object of the present invention is to provide an anticancer composition comprising an anticancer agent and SMG-1 as an active ingredient.

It is still another object of the present invention to provide an anticancer agent sensitivity enhancing composition comprising an expression vector comprising a polynucleotide encoding SMG-1 as an active ingredient.

In order to achieve the above object, the present invention provides a composition for enhancing the sensitivity of an anticancer agent comprising SMG-1 (Suppressor of Morphogenesis in Genitalia-1) as an active ingredient.

In one embodiment of the present invention, the anticancer agent may be sorafenib.

In one embodiment of the present invention, the SMG-1 may have the amino acid sequence of SEQ ID NO: 1.

In one embodiment of the present invention, the composition may be administered simultaneously, separately or sequentially with an anti-cancer agent.

In one embodiment of the present invention, the cancer is selected from the group consisting of lung cancer, stomach cancer, colon cancer, liver cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, , Breast cancer, fallopian tube carcinoma, endometrial carcinoma, cervical cancer, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, Or more selected from the group consisting of cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, renal or ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, CNS tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma, pituitary adenoma It can be solid cancer.

In one embodiment of the present invention, the cancer may be liver cancer.

The present invention also provides an anticancer composition comprising an anticancer agent and SMG-1 (Suppressor of Morphogenesis in Genitalia-1) as an active ingredient.

In one embodiment of the present invention, the anticancer agent may be sorafenib.

In one embodiment of the present invention, the SMG-1 may have the amino acid sequence of SEQ ID NO: 1.

In one embodiment of the present invention, the cancer is selected from the group consisting of lung cancer, stomach cancer, colon cancer, liver cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, , Breast cancer, fallopian tube carcinoma, endometrial carcinoma, cervical cancer, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, Or more selected from the group consisting of cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, renal or ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, CNS tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma, pituitary adenoma It can be solid cancer.

The present invention also provides a composition for promoting sensitivity to an anticancer agent comprising an expression vector comprising a polynucleotide encoding SMG-1 (Suppressor of Morphogenesis in Genitalia-1) as an active ingredient.

In one embodiment of the present invention, the polynucleotide may have the nucleotide sequence shown in SEQ ID NO: 2.

In one embodiment of the present invention, the anticancer agent may be sorafenib.

Since SMG-1 according to the present invention has a function related to the sensitivity enhancement of sorafenib to cancer cells, SMG-1 (Sorpenib), which is an anticancer agent, , The use of low concentration of sorapenib can inhibit the growth of cancer cells or induce death, which is useful for cancer treatment.

FIG. 1 is a graph showing the amount of SMG-1 mRNA measured by qPCR analysis in Hep3B cells transformed with SMG-1 siRNA.
FIG. 2 shows the results of protein gel blot analysis of the amount of SMG-1 protein in Hep3B cells transformed with SMG-1 siRNA.
FIG. 3 shows cell survival rates of Sorapanib treated with SMG-1 siRNA at different concentrations (0, 2, 5, 10 μM) in Hep3B cells.

In one aspect, the present invention relates to a composition for enhancing the sensitivity of an anticancer agent containing SMG-1 (Suppressor of Morphogenesis in Genitalia-1) as an active ingredient.

Suppressor of Morphogenesis in Genitalia-1 (SMG-1) is a serine / threonine kinase that plays a conservative role in nonsense-mediated mRNA decay (NMD) in insects and mammals. Human SMG- 1 is known to be involved in p53-mediated responses to genotoxic stress.

The function of SMG-1 is involved in nonsense mediated RNA decay (NMD), a member of phosphoinositide 3-kinase (PI3-kinase), which cleaves mRNA containing immature termination codons (Denning G, Jamieson L, Maquat LE, Thompson EA, Fields AP. Cloning of a novel phosphatidylinositol kinase-related kinase: characterization of the human SMG-1 RNA surveillance protein. J Biol Chem. 2001; 276 (25): 22709-14.); Caenohabditis elegans plays an important role in the survival and resistance of oxidative stress and plays an essential role in the embryogenesis process and plays an important role in activating p53 during DNA damage (Masse I, Molin L, Mouchiroud L, Vanhems P, Palladino F, Billaud M , et al., A novel role for the SMG-1 kinase in lifespan and oxidative stress resistance in Caenorhabditis elegans., 3 (10): e3354, PMCID: 2556085.); The role of negative regulators in inhibiting the function of Hypoxia-inducible factor (HIF) -alpha, which is involved in tumor angiogenesis and metastasis in hypoxia (Chen RQ, Yang QK, Chen YL, Oliveira VA, Dalton WS, Fearns C, et al .: Kinase siRNA screen identifies SMG-1 as a negative regulator of hypoxia-inducible factor-1alpha in hypoxia. J Biol Chem., 284 (25): 16752-8).

However, no studies have been conducted to date on the tolerance of anticancer drugs.

The present invention firstly revealed that SMG-1 is a gene related to tolerance (non-reactivity or resistance) to cancer cells of anticancer agent Sorapenib. Therefore, the present invention provides a novel use of SMG-1 as an anticancer drug sensitizer. have.

In the following examples of the present invention, the treatment of sorafenib with HepG2 cells transfected with SMG-1 siRNA resulted in a decrease in the cell survival rate depending on the concentration of sorapenib, whereas in the control group, the SMG- 1 knockdown showed that the survival rate of the cancer cells was not significantly changed. Thus, it was confirmed that the regulation of SMG-1 expression affects the susceptibility of the cancer cell line to sorafenib.

Therefore, the composition of the present invention containing SMG-1 as an active ingredient can effectively enhance anticancer drug sensitivity.

The term "siRNA" refers to small nucleic acid molecules of about 20 nucleotides in size that are capable of mediating RNA interference or gene silencing. Recently, RNA interference (RNAi) has been studied as a method for regulating protein expression at gene level. In general, siRNA specifically binds to mRNA having a complementary sequence to inhibit protein expression .

The term "anticancer agent" is a generic term for known drugs used in conventional cancer therapy that act on various metabolic pathways of cancer cells and exhibit cytotoxicity or cytostatic effects on cancer cells. Metabolic antagonists, botanical alkaloids, topoisomerase inhibitors, alkylating agents, anticancer antibiotics, hormones and other medicaments.

Examples of the anticancer agent to which the sensitivity can be increased include any anticancer agent sold on the market. For example, nitrocellulose, , Bortetanib, nilotinib, semathanib, conservative nib, acacitinib, cedaranib, lestaurintinib, trastuzumab, gepetinib, bortezomib, suminitinib, carboflatin, sorafenib, Cetuximine, cisplatin, cetuximab, viscum alum, asparaginase, tretinoin, hydroxycarbamide, dasatinib, estramerstin, gemtuzumab ozogamicin, ibritumomatocetane, heptaplatin, methylaminore But are not limited to, benzoic acid, ascorbic acid, amsacrine, alemtuzumab, procarbazine, alprostadil, holmium nitrate chitosan, gemcitabine, doxifluridine, femetrexed, tegafur, capecitabine, gimeracin, Azacitidine, methot But are not limited to, lecithin, uracil, cytarabine, fluorouracil, fluodagabine, enocitabine, flutamide, decitabine, mercaptopurine, thioguanine, cladribine, calmopar, ralitriptycide, docetaxel, paclitaxel, irinotecan , Bellotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine, tenifocide, doxorubicin, dirubicin, epirubicin, mitoxantrone, mitomycin, blormomycin, daunorubicin, But are not limited to, dactinomycin, firarubicin, aclarubicin, pemphromycin, temsirolimus, temozolomide, epidermal, iopospermide, cyclophosphamide, melphalan, altretamine, But are not limited to, thiazolidinediones, thiazolidinediones, thiazolidinediones, thiazolidinediones, thiazolidinediones, thiazolidinediones, thiazolidinediones, , Letrozole, borozol, bicaluta De, Romuald sustaining and may be a carboxylic estramustine.

In the examples of the present invention, resistance to sorafenib (non-reactivity or resistance) was confirmed.

In the present invention, SMG-1 may include not only a protein wild type having an enzyme activity but also a functional homolog having an amino acid homology of at least 90% and having an enzyme activity.

As used herein, the term "homology" refers to a similar degree to the amino acid sequence of a wild-type protein. The SMG-1 protein of the present invention is 70% or more homologous to a wild-type amino acid sequence defined by the sequence of SEQ ID NO: Or more, preferably 90% or more, and more preferably 95% or more. This comparison of homology can be performed using a visual program or a comparison program that is easy to purchase. Commercially available computer programs can calculate homology between two or more sequences as a percentage, and homology (%) can be calculated for adjacent sequences.

One of ordinary skill in the art will readily recognize that this artificial modification retains at least 90% homology and is an equivalent protein as long as it possesses enzyme activity in the present invention.

The SMG-1 protein according to the present invention may contain an amino acid sequence variant thereof as long as it retains the enzyme activity. By mutant herein is meant a protein having a sequence that differs by natural amino acid sequence and one or more amino acid residues by deletion, insertion, non-conservative or conservative substitution, or a combination thereof.

Such variants include functional homologues having substantially equivalent activity to the wild type or proteins having modifications that increase or decrease physicochemical properties. Preferably, the physicochemical properties of the protein are modified variants. For example, physical factors such as temperature, moisture, pH, electrolyte, reducing sugar, pressurization, drying, freezing, interfacial tension, lightning, repetition of freezing and thawing, high concentration conditions, and acid, alkali, neutral salt, organic solvent, , Oxidation-reduction agent, protease, and the like are increased in structural stability to the external environment. It may also be a mutant in which the enzyme activity is increased by a mutation in the amino acid sequence.

The SMG-1 protein according to the present invention may be produced directly by separating from an organism, chemically synthesized, or obtained using a gene recombination technique.

First, the SMG-1 protein according to the present invention can be prepared by directly isolating from an organism. The isolation and purification of the SMG-1 protein of the present invention contained in the cells can be carried out by a number of known methods.

The SMG-1 protein according to the present invention can be chemically synthesized. When chemically synthesized, it can be obtained by using a polypeptide synthesis method well known in the art. Polypeptides can be prepared using conventional stepwise liquid or solid phase synthesis, fractional condensation, F-MOC or T-BOC chemistry. In particular, the preferred method of preparing the polypeptide is by using solid phase syntheses. IL-1? Can be synthesized by a condensation reaction between protected amino acids in a conventional solid-phase method, starting from the C-terminus and progressing sequentially according to the sequence. After the condensation reaction, the protecting group and the carrier to which the C-terminal amino acid is linked can be removed by a known method such as acid decomposition or aminolysis. The above-mentioned polypeptide synthesis methods are described in detail in the relevant publications.

The SMG-1 protein according to the present invention may also be obtained using a gene recombination technique. In the case of using the recombinant technology, a polynucleotide (nucleic acid) encoding the SMG-1 protein of the present invention is inserted into an appropriate expression vector, and the vector is transformed into a host cell to express the SMG-1 protein of the present invention , And then recovering the protein from the host cell. The protein may be expressed in a selected host cell and then subjected to conventional biochemical separation techniques such as treatment with a protein precipitant (salting-out method), centrifugation, ultrasonic disruption, ultrafiltration, dialysis, (Gel filtration), adsorption chromatography, ion exchange chromatography, affinity chromatography, and the like. In order to separate proteins having high purity, they are used in combination.

In addition to the SMG-1 protein as an active ingredient, the composition for enhancing anticancer sensitivity of the present invention may be administered in a suitable formulation together with known carriers and diluents in the art, and may be administered parenterally, for example, Intramuscular injection, intraperitoneal injection, subcutaneous injection, suppository, and the like.

The formulations may be in the form of a solution or suspension of a suitable excipient, filler, binder, wetting agent, disintegrant, lubricant, surfactant, dispersant, buffer, preservative, solubilizer, disinfectant, sweetener, spice, analgesic, stabilizer, And the like.

Each of the formulations described above may comprise a pharmaceutically acceptable carrier or excipient. Specific examples of the carrier or the additive include water, a pharmaceutically acceptable organic solvent, collagen, polyvinyl alcohol, polyvinyl pyrrolidine, carboxyvinyl polymer, sodium alginate, water-soluble dextran, carboxymethyl sodium starch, pectin, , Gum arabic, casein, gelatin, agar, glycerol, propylene glycol, polyethylglycol, vaseline, paraffin, stearyl alcohol, stearic acid, human serum albumin, mannitol, sorbitol and lactic acid. One or more additives may be selected according to the form of preparation or may be combined as appropriate. Further, as a method for administering the composition of the present invention, topical administration to target cells can be performed in addition to conventional systemic administration such as intravenous, intraarterial administration, and administration methods combined with catheterization and surgical operation are used .

Such an anticancer agent sensitivity enhancing composition of the present invention can be administered simultaneously, separately or sequentially with an anticancer agent.

Examples of the cancer that can be treated by the composition of the present invention include lung cancer, stomach cancer, colon cancer, liver cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, Endometrioid cancer, thyroid cancer, pituitary cancer, adenocarcinoma, soft tissue sarcoma, urethra, uterine cancer, endometrioid cancer, endometrioid cancer, endometrioid cancer, The present invention relates to a method of treating cancer, cancer of the penis, cancer of the prostate, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvic carcinoma, CNS tumor, primary CNS lymphoma, spinal cord tumor, But is not limited thereto.

In one embodiment of the present invention, the composition of the present invention can be used for increasing the sensitivity of sorafenib, and the type of cancer that can exhibit the therapeutic effect is preferably hepatocellular carcinoma .

The dose of the composition for promoting sensitivity to an anti-cancer agent of the present invention may be suitably selected according to the patient's age, sex, weight, health condition, symptom of disease, administration time, administration method, mg may be administered. For example, therapeutically effective dosages can be determined initially using in vitro assays via cell culture. It will be possible in the art to determine the effective amount for treatment without undue experimentation and this information can be used to more accurately determine useful doses in humans.

In another aspect, the present invention relates to an anticancer agent and an anticancer composition comprising SMG-1 as an active ingredient.

The anticancer agent contained in the anticancer composition of the present invention may include all drugs used for the treatment of cancer, preferably sorafenib.

The anticancer composition of the present invention may contain an anticancer agent and an SMG-1 protein as active ingredients, and may be any type of medicament. For example, a combination containing two active ingredients may be constituted, or may be constituted as a single agent. Herein, the term " combination " refers to a combination of two or more active ingredients in one preparation, wherein a single preparation contains one active ingredient, wherein the active ingredients are classified according to their respective pharmacological and pharmacokinetic properties They may be manufactured and combined into different formulations. In the present invention, the therapeutic agent in the case where two active ingredients are monotherapeutic means a pharmaceutical agent that uses a combination of monotherapeutic agents each of which can be used singly. If the two active ingredients are monotherapy, they may be in the form of a kit in which the two components are in one go.

The anticancer composition of the present invention can be formulated by known methods together with suitable pharmaceutically acceptable carriers or excipients as described herein or below. Specific examples of such formulations include oral preparations such as soft capsules, hard capsules, tablets and syrups, injections, and external preparations.

Pharmaceutically acceptable carriers include any of the standard pharmaceutical carriers used in known formulations such as sterile solutions, tablets, coated tablets and capsules. Typically, such carriers are selected from the group consisting of polyvinylpyrrolidone, dextrin, starch, milk, sugar, certain types of clay, gelatin, stearic acid, talc, vegetable oils (for example, edible oils, cottonseeds, coconut oil, almond oil, (Such as crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and methylcellulose), such as vegetable oils, oil-in-water esters such as triglyceride glycerides, mineral oils, vaseline, animal fats and oils, , Or other known excipients. Such carriers may also include antioxidants, wetting agents, viscosity stabilizers, flavoring agents, coloring additives and other ingredients. The composition containing such a carrier can be formulated by a known method.

The anticancer composition of the present invention may be administered daily or intermittently, and the number of administration per day may be administered once or several times. The number of administrations of the two active ingredients may be the same or different. In addition, the pharmaceutical composition of the present invention can be administered in a pharmaceutically effective amount for the treatment of cancer. Typical dosage levels and ratios of anticancer agents (e.g., sorapenib) and SMG-1 material can be optimized using standard clinical techniques.

Examples of cancer that can be treated by the anticancer composition of the present invention include lung cancer, gastric cancer, colon cancer, liver cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer Endometrioid cancer, thyroid cancer, pituitary cancer, adenocarcinoma, soft tissue sarcoma, breast cancer, rectal cancer, rectum cancer, colorectal cancer, breast cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, Renal cell carcinoma, renal pelvic carcinoma, renal pelvic carcinoma, CNS tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma, pituitary adenoma, prostate cancer, And the like, preferably hepatocellular carcinoma.

In another aspect, the present invention relates to an anticancer agent for the manufacture of a medicament for the treatment of cancer and a use of a composition comprising SMG-1 as an active ingredient, preferably a composition comprising sorapenib and SMG-1 as an active ingredient . The anticancer agent according to the present invention and the composition of the present invention comprising SMG-1 as an active ingredient can be used for the preparation of medicines for the treatment of cancer.

In another aspect, the invention relates to a method of treating cancer comprising administering to a mammal a therapeutically effective amount of a pharmaceutical composition of the invention.

The term "mammal " as used herein refers to a mammal that is the subject of treatment, observation or experimentation, preferably a human.

As used herein, the term "therapeutically effective amount" refers to the amount of active ingredient that exhibits relieving, inhibiting, improving and / or curing effects on the disease (cancer) to be treated. In the present invention, when sorapenib is used as the anticancer agent, the dose of sorapenib and SMG-1 may vary depending on various factors, and the administration route thereof may be varied depending on the age of the patient, the period of administration, the weight, Whether oral or parenteral, by means of various factors such as the nature of the drug to be used, the type of the concomitant drug, and the like. It is also possible to administer them separately, simultaneously or sequentially, or separately over time.

The anticancer composition may be administered orally, subcutaneously, intraperitoneally, intrapulmonary, and intranasal, and is administered by a suitable method, including localized administration, if necessary, for local treatment. Non-oral injections include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Preferred modes of administration are intravenous, subcutaneous, intradermal, intramuscular, and drip.

In another aspect, the present invention relates to an anticancer agent sensitivity enhancing composition comprising as an active ingredient an expression vector comprising a polynucleotide encoding SMG-1 (Suppressor of Morphogenesis in Genitalia-1).

The polynucleotide encoding the SMG-1 protein of the present invention can be provided by a vector expressing it and expressed as a protein.

In the present invention, the polynucleotide encoding SMG-1 may be isolated from nature or artificially synthesized or modified. The nucleotide sequence encoding SMG-1 may be one in which at least one nucleotide base is modified by substitution, deletion or insertion And the protein expressed by such a modification should not contain a significant change in its biological activity. Such modifications include modifications to heterologous homologous genes.

Therefore, the polynucleotide encoding the SMG-1 protein is characterized by being represented by the nucleotide sequence of SEQ ID NO: 2, but is not limited thereto. The polynucleotide encoding the SMG-1 protein is preferably 70% or more, preferably 80% % Or more homology with the nucleotide sequence shown in SEQ ID NO.

Preferably, a polynucleotide encoding the SMG-1 protein of the present invention may be provided in the form of a recombinant expression vector operably linked to a vector expressing it. Expression vectors comprising SMG-1 polynucleotides include, but are not limited to, plasmids, phage, cosmid, viral vectors or other vectors known in the art. The vector may be self-replicating or integrated into the host DNA.

Polynucleotides encoding the SMG-1 protein may be combined with expression control sequences such as promoter / enhancer sequences and other sequences necessary for transcription, translation or processing. Regulatory sequences include tissue-specific regulatory and / or inducible sequences, as well as indicating constitutive expression of the nucleotide. The design of the expression vector may be determined by factors such as the host cell to be transfected, the level of expression desired, and the like.

Expression vectors expressing the SMG-1 protein of the present invention may be non-viral vectors or viral vectors.

As the non-viral vector, a plasmid is representative. The plasmid expression vector is a method for transferring plasmid DNA directly to human cells using an approved FDA-approved gene transfer method which can be used for human. Unlike the viral vector, the plasmid DNA has an advantage that it can be homogeneously purified. As the plasmid expression vector that can be used in the present invention, mammalian expression plasmids known in the art can be used. Examples include, but are not limited to pRK5 (European Patent No. 307,247), pSV16B (International Patent Publication No. 91/08291) and pVL1392 (PharMingen).

In addition, a viral vector can be used as an expression vector expressing the SMG-1 protein of the present invention. Viral vectors include, for example, retroviruses, adenoviruses, adenovirus-associated viruses, herpes viruses and avipoxviruses. The viral vector must meet the following criteria: (1) it should be able to infect the desired cell, so that a viral vector with an appropriate host range has to be selected; (2) And (3) the vector must be safe for the host.

The retroviral vector is constructed such that all of the viral genes have been removed or altered so that the non-viral proteins are made in cells infected with the viral vector. The main advantage of retroviral vectors for gene therapy is that they transfer a large amount of genes into the cloned cells,

And does not result in subsequent infections following gene transfection. FDA-approved retroviral vectors were prepared using PA317 amphotropic retroviral packaging cells (Miller, A.D. and Buttimore, C., Molec. Cell Biol., 6: 2895-2902, 1986).

Non-retroviral vectors include the adenoviruses mentioned above. The main advantage of adenoviruses is the ability to carry large quantities of DNA fragments (36 kb genome) and to infect very high reverse non-cloned cells. Herpesviruses may also be useful for human gene therapy (Wolfe, J. H., et al., Nature Genetics, 1: 379-384, 1992). In addition, suitable known viral vectors may be used in the pharmaceutical compositions of the present invention.

Other viral vectors that may be used for gene delivery into cells include, but are not limited to, murine leukemia virus (MLV), JC, SV40, polyoma, Epstein-Barr virus papilloma virus, vaccinia, poliovirus, herpes virus, Viruses, other human and animal viruses.

The expression vector according to the present invention can be introduced into cells using methods known in the art. But are not limited to, transient transfection, microinjection, transduction, cell fusion, calcium phosphate precipitation, liposome-mediated transfection, DEAE dextran- DEAE Dextran-mediated transfection, polybrene-mediated transfection, electropora tion, gene gun, and other notifications for introducing nucleic acids into cells (Wu et al., J. Bio. Chem., 267: 963-967, 1992; Wu and Wu, J. Bio. Chem., 263: 14621-14624, 1988) .

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are for further illustrating the present invention, and the scope of the present invention is not limited to these examples.

< Example  1>

SMG -One siRNA Lt; RTI ID = 0.0 &gt; SMG -1 expression level measurement

In order to confirm whether SMG-1 siRNA can effectively knockdown SMG-1, the present inventors firstly transfected hepatocellular carcinoma Hep3B cells with SMG-1 siRNA having the sequence of SEQ ID NO: 3, The expression level of SMG-1 was measured at the transcription level and the protein level.

<1-1> Liver cancer cell line  Culture and SMG -One siRNA  Ready

Hep3B cells were distributed at a concentration of 1 × 10 ⁶ / cm ₂ (American Tissue Culture Collection) and cultured in DMEM medium supplemented with 10% FBS supplemented with penicillin-streptomycin (10 IU / ml) incubator: 5% CO ₂ in air). The Stealth TM RNAi double helix used in the present invention was commercially synthesized by Invitrogen Life Technologies Inc. The Stealth TM RNAi (HSS118096, HSS118097, HSS11808) used in the present invention was designed for the target of the coding region of the human SMG-1 mRNA sequence (NCBI Reference Sequence: NM_015092.3).

<1-2> SMG -One siRNA Transformation using

First, Hep3B cells cultured using DMEM (Invitrogen Life Technology Inc.) containing 10% FBS (Invitrogen Life Technology Inc.) were dispensed in a 60 mm dish at a concentration of 4 × 10 ⁵ . The cells were transformed with the Stealth TM RNAi double helix (Cat No / Lot 10620318 / 205814B02 and 10620319 / 205814B03) purchased from Invitrogen using hiperfect transfection reagent (Qiagen) according to the protocol instructions (see Table 1 below) . At this time, the final concentration of Stealth TM RNAi was 50 nM and the control group was Med GC (Invitrogen Life Technology Inc.) used as siRNA negative control group.

The StealthTM RNAi double helix used in the present invention Cat No / Lot type order 10620318/205814 B02 RNA GAGGAUGACCCUAGGCUGCAUUUAA 10620319/205814 B03 RNA UUAAAUGCAGCCUAGGGUCAUCCUC

<1-3> Reverse transcription  And real time qPCR  analysis

In this experiment, in order to investigate whether expression of SMG-1 is suppressed at the gene level according to SMG-1 siRNA transformation, the expression level of SMG-1 gene in the transfected cells prepared in Example <1-2> qPCR was performed and analyzed.

Total mRNA was extracted from Hep3B cells using the TRIZOL kit (Invitrogen) according to the manufacturer's instructions. For real-time quantitative analysis, the first cDNA strand was prepared using Reverse Transcription Kit (Invitrogen), and the smg1 taqman probes were designed by Applied Biosystems. Real-time PCR was performed using the Taqman fast reagent starter kit (ABI) on the CABI 7500 fast real-time PCR system. The expression results were standardized quantitatively using GAPDH as an internal control.

As a result, as shown in Fig. 1, SMG-1 mRNA was significantly inhibited in Hep3B cells transfected with SMG-1 siRNA, and expression of SMG-1 gene was proportional to the concentration of SMG-1 siRNA It was confirmed that it was suppressed at the transcription level.

<1-4> Protein gel Blat  analysis

In order to measure the amount of SMG-1 protein produced in the transfected cells prepared in Example <1-2>, Hep3B cells transformed with PBS were washed and treated with a lysis buffer to obtain a supernatant The proteins were then separated using NuPAGE Novex 3-8% Tri-Acetate (Invitrogen). All primary antibodies were diluted with 3% BSA in Tris buffered saline (TBS-T) containing 0.1% Tween according to the following concentrations: anti-beta-actin (1: 1000, Cell Signaling), anti- 1: 500, Cell Signaling) and secondary HRP conjugated antibody (Cell signaling). HRP was detected using Immunobilon Western chemiluminescent HRP substrate kit (Millipore) and images were scanned using Bio-Rad ChemiDoc XRS System.

As a result, as shown in Fig. 2, almost no SMG-1 protein was detected in Hep3B cells transfected with SMG-1 siRNA, It is possible to confirm that knockdown is effectively performed.

< Example  2>

SMG -1 &lt; / RTI &gt; Sora Fenib's  Measurement of cell viability by concentration treatment

In order to confirm whether SMG-1 gene is associated with sorafenib resistance (non-reactivity or resistance), the present inventors measured the cell survival rate of the cancer cells after treatment with sorapenib in the Hep3B cell line transformed with SMG-1 siRNA Were measured.

In detail, Hep3B cells transfected with SMG-1 siRNA were treated with 0, 2, 5, and 10 μmol of sorapenib and cultured for 48 hours. Cell viability was measured using the EZ-CyTox cell viability assay kit (Daeillab, Were measured. EZ-CyTox solution (10 μL) was added to each of the 96 wells in which the cells were cultured, and then cultured at 37 ° C. for 2 hours. Absorbance was measured using an ELISA reader at 450 nm (Microplate reader, Bio-Rad). Cell viability was expressed as relative percent relative to vehicle-treated cells (untransformed cells) defined as 100% survival.

As a result, as shown in FIG. 3, the survival rate of liver cancer cells was not significantly changed in the experimental group in which SMG-1 was knocked down using siRNA, while the control group had a decrease in cell survival rate depending on the concentration of sorapenib. Therefore, it was confirmed that SMG-1 expression control affects the resistance (non-reactivity or resistance) to the cancer cell line of sorapenib. Especially, when the expression or activity of SMG-1 is inhibited, anticancer drugs such as sorafenib In contrast, when SMG-1 was expressed, the cell death rate of cancer cells was increased dependently on the concentration of sorafenib.

The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

SMG-1: Suppressor of Morphogenesis in Genitalia-1

                         SEQUENCE LISTING <110> CATHOLIC UNIVERSITY INDUSTRY ACADEMIC COOPERATION        FOUNDATION   <120> Composition for Enhancing Sensitivity to Anti-cancer agent        Compressing of Suppressor of Morphogenesis in Genitalia-1 <130> PN1204-174 <160> 2 <170> PatentIn version 3.2 <210> 1 <211> 3661 <212> PRT <213> Homo sapiens <400> 1 Met Ser Arg Arg Ala Pro Gly Ser Arg Leu Ser Ser Gly Gly Gly Gly 1 5 10 15 Gly Gly Thr Lys Tyr Pro Arg Ser Trp Asn Asp Trp Gln Pro Arg Thr             20 25 30 Asp Ser Ala Ser Ala Asp Pro Asp Asn Leu Lys Tyr Ser Ser Ser Arg         35 40 45 Asp Arg Gly Gly Ser Ser Ser Tyr Gly Leu Gln Pro Ser Asn Ser Ala     50 55 60 Val Val Ser Arg Gln Arg His Asp Asp Thr Arg Val His Ala Asp Ile 65 70 75 80 Gln Asn Asp Glu Lys Gly Gly Tyr Ser Val Asn Gly Gly Ser Gly Glu                 85 90 95 Asn Thr Tyr Gly Arg Lys Ser Leu Gly Gln Glu Leu Arg Val Asn Asn             100 105 110 Val Thr Ser Pro Glu Phe Thr Ser Val Gln His Gly Ser Arg Ala Leu         115 120 125 Ala Thr Lys Asp Met Arg Lys Ser Gln Glu Arg Ser Ser Met Ser Tyr Ser     130 135 140 Asp Glu Ser Arg Leu Ser Asn Leu Leu Arg Arg Ile Thr Arg Glu Asp 145 150 155 160 Asp Arg Asp Arg Arg Leu Ala Thr Val Lys Gln Leu Lys Glu Phe Ile                 165 170 175 Gln Gln Pro Glu Asn Lys Leu Val Leu Val Lys Gln Leu Asp Asn Ile             180 185 190 Leu Ala Ala Val His Asp Val Leu Asn Glu Ser Ser Lys Leu Leu Gln         195 200 205 Glu Leu Arg Gln Glu Gly Ala Cys Cys Leu Gly Leu Leu Cys Ala Ser     210 215 220 Leu Ser Tyr Glu Ala Glu Lys Ile Phe Lys Trp Ile Phe Ser Lys Phe 225 230 235 240 Ser Ser Ala Lys Asp Glu Val Lys Leu Leu Tyr Leu Cys Ala Thr                 245 250 255 Tyr Lys Ala Leu Glu Thr Val Gly Glu Lys Lys Ala Phe Ser Ser Val             260 265 270 Met Gln Leu Val Met Thr Ser Leu Gln Ser Ile Leu Glu Asn Val Asp         275 280 285 Thr Pro Glu Leu Leu Cys Lys Cys Val Lys Cys Ile Leu Leu Val Ala     290 295 300 Arg Cys Tyr Pro His Ile Phe Ser Thr Asn Phe Arg Asp Thr Val Asp 305 310 315 320 Ile Leu Val Gly Trp His Ile Asp His Thr Gln Lys Pro Ser Leu Thr                 325 330 335 Gln Gln Val Ser Gly Trp Leu Gln Ser Leu Glu Pro Phe Trp Val Ala             340 345 350 Asp Leu Ala Phe Ser Thr Thr Leu Leu Gly Gln Phe Leu Glu Asp Met         355 360 365 Glu Ala Tyr Ala Glu Asp Leu Ser His Val Ala Ser Gly Glu Ser Val     370 375 380 Asp Glu Asp Val Pro Pro Pro Ser Val Ser Leu Pro Lys Leu Ala Ala 385 390 395 400 Leu Leu Arg Val Phe Ser Thr Val Val Arg Ser Ser Gly Glu Arg Phe                 405 410 415 Ser Pro Ile Arg Gly Pro Pro Ile Thr Glu Ala Tyr Val Thr Asp Val             420 425 430 Leu Tyr Arg Val Met Arg Cys Val Thr Ala Ala Asn Gln Val Phe Phe         435 440 445 Ser Glu Ala Val Leu Thr Ala Ala Asn Glu Cys Val Gly Val Leu Leu     450 455 460 Gly Ser Leu Asp Pro Ser Met Thr Ile His Cys Asp Met Val Ile Thr 465 470 475 480 Tyr Gly Leu Asp Gln Leu Glu Asn Cys Gln Thr Cys Gly Thr Asp Tyr                 485 490 495 Ile Ile Ser Val Leu Asn Leu Leu Thr Leu Ile Val Glu Gln Ile Asn             500 505 510 Thr Lys Leu Pro Ser Ser Phe Val Glu Lys Leu Phe Ile Pro Ser Ser         515 520 525 Lys Leu Leu Phe Leu Arg Tyr His Lys Glu Lys Glu Val Val Ala Val     530 535 540 Ala His Ala Val Tyr Gln Ala Val Leu Ser Leu Lys Asn Ile Pro Val 545 550 555 560 Leu Glu Thr Ala Tyr Lys Leu Ile Leu Gly Glu Met Thr Cys Ala Leu                 565 570 575 Asn Asn Leu Leu His Ser Leu Gln Leu Pro Glu Ala Cys Ser Glu Ile             580 585 590 Lys His Glu Ala Phe Lys Asn His Val Phe Asn Val Asp Asn Ala Lys         595 600 605 Phe Val Val Ile Phe Asp Leu Ser Ala Leu Thr Thr Ile Gly Asn Ala     610 615 620 Lys Asn Ser Leu Ile Gly Met Trp Ala Leu Ser Pro Thr Val Phe Ala 625 630 635 640 Leu Leu Ser Lys Asn Leu Met Ile Val His Ser Asp Leu Ala Val His                 645 650 655 Phe Pro Ala Ile Gln Tyr Ala Val Leu Tyr Thr Leu Tyr Ser His Cys             660 665 670 Thr Arg His Asp His Phe Ile Ser Ser Ser Leu Ser Ser Ser Ser Pro         675 680 685 Ser Leu Phe Asp Gly Ala Val Ile Ser Thr Val Thr Thr Ala Thr Lys     690 695 700 Lys His Phe Ser Ile Ile Leu Asn Leu Leu Gly Ile Leu Leu Lys Lys 705 710 715 720 Asp Asn Leu Asn Gln Asp Thr Arg Lys Leu Leu Met Thr Trp Ala Leu                 725 730 735 Glu Ala Ala Val Leu Met Lys Lys Ser Glu Thr Tyr Ala Pro Leu Phe             740 745 750 Ser Leu Pro Ser Phe His Lys Phe Cys Lys Gly Leu Leu Ala Asn Thr         755 760 765 Leu Val Glu Asp Val Asn Ile Cys Leu Gln Ala Cys Ser Ser Leu His     770 775 780 Ala Leu Ser Ser Leu Pro Asp Leu Leu Gln Arg Cys Val Asp 785 790 795 800 Val Cys Arg Val Gln Leu Val His Ser Gly Thr Arg Ile Arg Gln Ala                 805 810 815 Phe Gly Lys Leu Leu Lys Ser Ile Pro Leu Asp Val Val Leu Ser Asn             820 825 830 Asn Asn His Thr Glu Ile Gln Glu Ile Ser Leu Ala Leu Arg Ser His         835 840 845 Met Ser Lys Ala Pro Ser Asn Thr Phe His Pro Gln Asp Phe Ser Asp     850 855 860 Val Ile Ser Phe Ile Leu Tyr Gly Asn Ser His Arg Thr Gly Lys Asp 865 870 875 880 Asn Trp Leu Glu Arg Leu Phe Tyr Ser Cys Gln Arg Leu Asp Lys Arg                 885 890 895 Asp Gln Ser Thr Ile Pro Arg Asn Leu Leu Lys Thr Asp Ala Val Leu             900 905 910 Trp Gln Trp Ala Ile Trp Glu Ala Ala Gln Phe Thr Val Leu Ser Lys         915 920 925 Leu Arg Thr Pro Leu Gly Arg Ala Gln Asp Thr Phe Gln Thr Ile Glu     930 935 940 Gly Ile Ile Arg Ser Leu Ala Ala His Thr Leu Asn Pro Asp Gln Asp 945 950 955 960 Val Ser Gln Trp Thr Thr Ala Asp Asn Asp Glu Gly His Gly Asn Asn                 965 970 975 Gln Leu Arg Leu Val Leu Leu Leu Gln Tyr Leu Glu Asn Leu Glu Lys             980 985 990 Leu Met Tyr Asn Ala Tyr Glu Gly Cys Ala Asn Ala Leu Thr Ser Pro         995 1000 1005 Pro Lys Val Ile Arg Thr Phe Phe Tyr Thr Asn Arg Gln Thr Cys     1010 1015 1020 Gln Asp Trp Leu Thr Arg Ile Arg Leu Ser Ile Met Arg Val Gly     1025 1030 1035 Leu Leu Ala Gly Gln Pro Ala Val Thr Val Arg His Gly Phe Asp     1040 1045 1050 Leu Leu Thr Glu Met Lys Thr Thr Ser Leu Ser Gln Gly Asn Glu     1055 1060 1065 Leu Glu Val Thr Ile Met Met Val Val Glu Ala Leu Cys Glu Leu     1070 1075 1080 His Cys Pro Glu Ala Ile Gln Gly Ile Ala Val Trp Ser Ser Ser     1085 1090 1095 Ile Val Gly Lys Asn Leu Leu Trp Ile Asn Ser Val Ala Gln Gln     1100 1105 1110 Ala Glu Gly Arg Phe Glu Lys Ala Ser Val Glu Tyr Gln Glu His     1115 1120 1125 Leu Cys Ala Met Thr Gly Val Asp Cys Cys Ile Ser Ser Phe Asp     1130 1135 1140 Lys Ser Val Leu Thr Leu Ala Asn Ala Gly Arg Asn Ser Ala Ser     1145 1150 1155 Pro Lys His Ser Leu Asn Gly Glu Ser Arg Lys Thr Val Leu Ser     1160 1165 1170 Lys Pro Thr Asp Ser Ser Pro Glu Val Ile Asn Tyr Leu Gly Asn     1175 1180 1185 Lys Ala Cys Glu Cys Tyr Ile Ser Ile Ala Asp Trp Ala Ala Val     1190 1195 1200 Gln Glu Trp Gln Asn Ale I His Asp Leu Lys Lys Ser Thr Ser     1205 1210 1215 Ser Thr Ser Leu Asn Leu Lys Ala Asp Phe Asn Tyr Ile Lys Ser     1220 1225 1230 Leu Ser Ser Phe Glu Ser Gly Lys Phe Val Glu Cys Thr Glu Gln     1235 1240 1245 Leu Glu Leu Leu Pro Gly Glu Asn Ile Asn Leu Leu Ala Gly Gly     1250 1255 1260 Ser Lys Glu Lys Ile Asp Met Lys Lys Leu Leu Pro Asn Met Leu     1265 1270 1275 Ser Pro Asp Pro Arg Glu Leu Gln Lys Ser Ile Glu Val Gln Leu     1280 1285 1290 Leu Arg Ser Ser Cys Leu Ala Thr Ala Leu Asn Pro Ile Glu     1295 1300 1305 Gln Asp Gln Lys Trp Gln Ser Ile Thr Glu Asn Val Val Lys Tyr     1310 1315 1320 Leu Lys Gln Thr Ser Arg Ile Ala Ile Gly Pro Leu Arg Leu Ser     1325 1330 1335 Thr Leu Thr Val Ser Gln Ser Leu Pro Val Leu Ser Thr Leu Gln     1340 1345 1350 Leu Tyr Cys Ser Ser Ale Leu Glu Asn Thr Ser Ser Asn Arg Leu     1355 1360 1365 Ser Thr Glu Asp Cys Leu Ile Pro Leu Phe Ser Glu Ala Leu Arg     1370 1375 1380 Ser Cys Lys Gln His Asp Val Arg Pro Trp Met Gln Ala Leu Arg     1385 1390 1395 Tyr Thr Met Tyr Gln Asn Gln Leu Leu Glu Lys Ile Lys Glu Gln     1400 1405 1410 Thr Val Pro Ile Arg Ser His Leu Met Glu Leu Gly Leu Thr Ala     1415 1420 1425 Ala Lys Phe Ala Arg Lys Arg Gly Asn Val Ser Leu Ala Thr Arg     1430 1435 1440 Leu Leu Ala Gln Cys Ser Glu Val Gln Leu Gly Lys Thr Thr Thr     1445 1450 1455 Ala Gln Asp Leu Val Gln His Phe Lys Lys Leu Ser Thr Gln Gly     1460 1465 1470 Gln Val Asp Glu Lys Trp Gly Pro Glu Leu Asp Ile Glu Lys Thr     1475 1480 1485 Lys Leu Leu Tyr Thr Ala Gly Gln Ser Thr His Ala Met Glu Met     1490 1495 1500 Leu Ser Ser Cys Ala Ile Ser Phe Cys Lys Ser Val Lys Ala Glu     1505 1510 1515 Tyr Ala Val Ala Lys Ser Ile Leu Thr Leu Ala Lys Trp Ile Gln     1520 1525 1530 Ala Glu Trp Lys Glu Ile Ser Gly Gln Leu Lys Gln Val Tyr Arg     1535 1540 1545 Ala Gln His Gln Gln Asn Phe Thr Gly Leu Ser Thr Leu Ser Lys     1550 1555 1560 Asn Ile Leu Thr Leu Ile Glu Leu Pro Ser Val Asn Thr Met Glu     1565 1570 1575 Glu Glu Tyr Pro Arg Ile Glu Ser Glu Ser Thr Val His Ile Gly     1580 1585 1590 Val Gly Glu Pro Asp Phe Ile Leu Gly Gln Leu Tyr His Leu Ser     1595 1600 1605 Ser Val Gln Ala Pro Glu Val Ala Lys Ser Trp Ala Ala Leu Ala     1610 1615 1620 Ser Trp Ala Tyr Arg Trp Gly Arg Lys Val Val Asp Asn Ala Ser     1625 1630 1635 Gln Gly Glu Gly Val Arg Leu Leu Pro Arg Glu Lys Ser Glu Val     1640 1645 1650 Gln Asn Leu Leu Pro Asp Thr Ile Thr Glu Glu Glu Lys Glu Arg     1655 1660 1665 Ile Tyr Gly Ile Leu Gly Gln Ala Val Cys Arg Pro Ala Gly Ile     1670 1675 1680 Gln Asp Glu Asp Ile Thr Leu Gln Ile Thr Glu Ser Glu Asp Asn     1685 1690 1695 Glu Asp Asp Met Val Asp Val Ile Trp Arg Gln Leu Ile Ser     1700 1705 1710 Ser Cys Pro Trp Leu Ser Glu Leu Asp Glu Ser Ala Thr Glu Gly     1715 1720 1725 Val Ile Lys Val Trp Arg Lys Val Val Asp Arg Ile Phe Ser Leu     1730 1735 1740 Tyr Lys Leu Ser Cys Ser Ala Tyr Phe Thr Phe Leu Lys Leu Asn     1745 1750 1755 Ala Gly Gln Ile Pro Leu Asp Glu Asp Asp Pro Arg Leu His Leu     1760 1765 1770 Ser His Arg Val Glu Gln Ser Thr Asp Asp Met Ile Val Met Ala     1775 1780 1785 Thr Leu Arg Leu Leu Arg Leu Leu Val Lys His Ala Gly Glu Leu     1790 1795 1800 Arg Gln Tyr Leu Glu His Gly Leu Glu Thr Thr Pro Thr Ala Pro     1805 1810 1815 Trp Arg Gly Ile Ile Pro Gln Leu Phe Ser Arg Leu Asn His Pro     1820 1825 1830 Glu Val Tyr Val Arg Gln Ser Ile Cys Asn Leu Leu Cys Arg Val     1835 1840 1845 Ala Gln Asp Ser Pro His Leu Ile Leu Tyr Pro Ala Ile Val Gly     1850 1855 1860 Thr Ile Ser Leu Ser Ser Glu Ser Gln Ala Ser Gly Asn Lys Phe     1865 1870 1875 Ser Thr Ala Ile Pro Thr Leu Leu Gly Asn Ile Gln Gly Glu Glu     1880 1885 1890 Leu Leu Val Ser Glu Cys Glu Gly Gly Ser Pro Pro Ala Ser Gln     1895 1900 1905 Asp Ser Asn Lys Asp Glu Pro Lys Ser Gly Leu Asn Glu Asp Gln     1910 1915 1920 Ala Met Met Gln Asp Cys Tyr Ser Lys Ile Val Asp Lys Leu Ser     1925 1930 1935 Ser Ala Asn Pro Thr Met Val Leu Gln Val Gln Met Leu Val Ala     1940 1945 1950 Glu Leu Arg Arg Val Thr Val Leu Trp Asp Glu Leu Trp Leu Gly     1955 1960 1965 Val Leu Leu Gln Gln His Met Tyr Val Leu Arg Arg Ile Gln Gln     1970 1975 1980 Leu Glu Asp Glu Val Lys Arg Val Gln Asn Asn Asn Thr Leu Arg     1985 1990 1995 Lys Glu Glu Lys Ile Ala Ile Met Arg Glu Lys His Thr Ala Leu     2000 2005 2010 Met Lys Pro Ile Val Phe Ala Leu Glu His Val Arg Ser Ile Thr     2015 2020 2025 Ala Ala Pro Ala Glu Thr Pro His Glu Lys Trp Phe Gln Asp Asn     2030 2035 2040 Tyr Gly Asp Ala Ile Glu Asn Ala Leu Glu Lys Leu Lys Thr Pro     2045 2050 2055 Leu Asn Pro Ala Lys Pro Gly Ser Ser Trp Ile Pro Phe Lys Glu     2060 2065 2070 Ile Met Leu Ser Leu Gln Gln Arg Ala Gln Lys Arg Ala Ser Tyr     2075 2080 2085 Ile Leu Arg Leu Glu Glu Ile Ser Pro Trp Leu Ala Ala Met Thr     2090 2095 2100 Asn Thr Glu Ile Ala Leu Pro Gly Glu Val Ser Ala Arg Asp Thr     2105 2110 2115 Val Thr Ile His Ser Val Gly Gly Thr Ile Thr Ile Leu Pro Thr     2120 2125 2130 Lys Thr Lys Pro Lys Lys Leu Leu Phe Leu Gly Ser Asp Gly Lys     2135 2140 2145 Ser Tyr Pro Tyr Leu Phe Lys Gly Leu Glu Asp Leu His Leu Asp     2150 2155 2160 Glu Arg Ile Met Gln Phe Leu Ser Ile Val Asn Thr Met Phe Ala     2165 2170 2175 Thr Ile Asn Arg Gln Glu Thr Pro Arg Phe His Ala Arg His Tyr     2180 2185 2190 Ser Val Thr Pro Leu Gly Thr Arg Ser Gly Leu Ile Gln Trp Val     2195 2200 2205 Asp Gly Ala Thr Pro Leu Phe Gly Leu Tyr Lys Arg Trp Gln Gln     2210 2215 2220 Arg Glu Ala Ala Leu Gln Ala Gln Lys Ala Gln Asp Ser Tyr Gln     2225 2230 2235 Thr Pro Gln Asn Pro Gly Ile Val Pro Arg Ser Ser Glu Leu Tyr     2240 2245 2250 Tyr Ser Lys Ile Gly Pro Ala Leu Lys Thr Val Gly Leu Ser Leu     2255 2260 2265 Asp Val Ser Arg Arg Asp Trp Pro Leu His Val Met Lys Ala Val     2270 2275 2280 Leu Glu Glu Leu Glu Ala Thr Pro Pro Asn Leu Leu Ala Lys     2285 2290 2295 Glu Leu Trp Ser Ser Cys Thr Thr Pro Asp Glu Trp Trp Arg Val     2300 2305 2310 Thr Gln Ser Tyr Ala Arg Ser Thr Ala Val Met Ser Ser Met Val Gly     2315 2320 2325 Tyr Ile Ile Gly Leu Gly Asp Arg His Leu Asp Asn Val Leu Ile     2330 2335 2340 Asp Met Thr Thr Gly Glu Val Val His Ile Asp Tyr Asn Val Cys     2345 2350 2355 Phe Glu Lys Gly Lys Ser Leu Arg Val Pro Glu Lys Val Pro Phe     2360 2365 2370 Arg Met Thr Gln Asn Ile Glu Thr Ala Leu Gly Val Thr Gly Val     2375 2380 2385 Glu Gly Val Phe Arg Leu Ser Cys Glu Gln Val Leu His Ile Met     2390 2395 2400 Arg Arg Gly Arg Glu Thr Leu Leu Thr Leu Leu Glu Ala Phe Val     2405 2410 2415 Tyr Asp Pro Leu Val Asp Trp Thr Ala Gly Gly Glu Ala Gly Phe     2420 2425 2430 Ala Gly Ala Val Tyr Gly Gly Gly Gly Gln Gln Ala Glu Ser Lys     2435 2440 2445 Gln Ser Lys Arg Glu Met Glu Arg Glu Ile Thr Arg Ser Leu Phe     2450 2455 2460 Ser Ser Arg Val Ala Glu Ile Lys Val Asn Trp Phe Lys Asn Arg     2465 2470 2475 Asp Glu Met Leu Val Val Leu Pro Lys Leu Asp Gly Ser Leu Asp     2480 2485 2490 Glu Tyr Leu Ser Leu Gln Glu Gln Leu Thr Asp Val Glu Lys Leu     2495 2500 2505 Gln Gly Lys Leu Leu Glu Glu Ile Glu Phe Leu Glu Gly Ala Glu     2510 2515 2520 Gly Val Asp His Pro Ser His Thr Leu Gln His Arg Tyr Ser Glu     2525 2530 2535 His Thr Gln Leu Gln Thr Gln Gln Arg Ala Val Gln Glu Ala Ile     2540 2545 2550 Gln Val Lys Leu Asn Glu Phe Glu Gln Trp Ile Thr His Tyr Gln     2555 2560 2565 Ala Ala Phe Asn Asn Leu Glu Ala Thr Gln Leu Ala Ser Leu Leu     2570 2575 2580 Gln Glu Ile Ser Thr Gln Met Asp Leu Gly Pro Pro Ser Tyr Val     2585 2590 2595 Pro Ala Thr Ala Phe Leu Gln Asn Ala Gly Gln Ala His Leu Ile     2600 2605 2610 Ser Gln Cys Glu Gln Leu Glu Gly Glu Val Gly Ala Leu Leu Gln     2615 2620 2625 Gln Arg Arg Ser Val Leu Arg Gly Cys Leu Glu Gln Leu His His     2630 2635 2640 Tyr Ala Thr Val Ala Leu Gln Tyr Pro Lys Ala Ile Phe Gln Lys     2645 2650 2655 His Arg Ile Glu Gln Trp Lys Thr Trp Met Glu Glu Leu Ile Cys     2660 2665 2670 Asn Thr Thr Val Glu Arg Cys Gln Glu Leu Tyr Arg Lys Tyr Glu     2675 2680 2685 Met Gln Tyr Ala Pro Gln Pro Pro Thr Val Cys Gln Phe Ile     2690 2695 2700 Thr Ala Thr Glu Met Thr Leu Gln Arg Tyr Ala Ala Asp Ile Asn     2705 2710 2715 Ser Arg Leu Ile Arg Gln Val Glu Arg Leu Lys Gln Glu Ala Val     2720 2725 2730 Thr Val Pro Val Cys Glu Asp Gln Leu Lys Glu Ile Glu Arg Cys     2735 2740 2745 Ile Lys Val Phe Leu His Glu Asn Gly Glu Glu Gly Ser Leu Ser     2750 2755 2760 Leu Ala Ser Val Ile Ile Ser Ala Leu Cys Thr Leu Thr Arg Arg     2765 2770 2775 Asn Leu Met Met Glu Gly Ala Ala Ser Ser Ala Gly Glu Gln Leu     2780 2785 2790 Val Asp Leu Thr Ser Arg Asp Gly Ala Trp Phe Leu Glu Glu Leu     2795 2800 2805 Cys Ser Met Ser Gly Asn Val Thr Cys Leu Val Gln Leu Leu Lys     2810 2815 2820 Gln Cys His Leu Val Pro Gln Asp Leu Asp Ile Pro Asn Pro Met     2825 2830 2835 Glu Ala Ser Glu Thr Val His Leu Ala Asn Gly Val Tyr Thr Ser     2840 2845 2850 Leu Gln Glu Leu Asn Ser Asn Phe Arg Gln Ile Ile Phe Pro Glu     2855 2860 2865 Ala Leu Arg Cys Leu Met Lys Gly Glu Tyr Thr Leu Glu Ser Met     2870 2875 2880 Leu His Glu Leu Asp Gly Leu Ile Glu Gln Thr Thr Asp Gly Val     2885 2890 2895 Pro Leu Gln Thr Leu Val Glu Ser Leu Gln Ala Tyr Leu Arg Asn     2900 2905 2910 Ala Ala Met Gly Leu Glu Glu Glu Thr His Ala His Tyr Ile Asp     2915 2920 2925 Val Ala Arg Leu Leu His Ala Gln Tyr Gly Glu Leu Ile Gln Pro     2930 2935 2940 Arg Asn Gly Ser Val Asp Glu Thr Pro Lys Met Ser Ala Gly Gln     2945 2950 2955 Met Leu Leu Val Ala Phe Asp Gly Met Phe Ala Gln Val Glu Thr     2960 2965 2970 Ala Phe Ser Leu Leu Val Glu Lys Leu Asn Lys Met Glu Ile Pro     2975 2980 2985 Ile Ala Trp Arg Lys Ile Asp Ile Ile Arg Glu Ala Arg Ser Thr     2990 2995 3000 Gln Val Asn Phe Phe Asp Asp Asp Asn His Arg Gln Val Leu Glu     3005 3010 3015 Glu Ile Phe Phe Leu Lys Arg Leu Gln Thr Ile Lys Glu Phe Phe     3020 3025 3030 Arg Leu Cys Gly Thr Phe Ser Lys Thr Leu Ser Gly Ser Ser Ser     3035 3040 3045 Leu Glu Asp Gln Asn Thr Val Asn Gly Pro Val Gln Ile Val Asn     3050 3055 3060 Val Lys Thr Leu Phe Arg Asn Ser Cys Phe Ser Glu Asp Gln Met     3065 3070 3075 Ala Lys Pro Ile Lys Ala Phe Thr Ala Asp Phe Val Arg Gln Leu     3080 3085 3090 Leu Ile Gly Leu Pro Asn Gln Ala Leu Gly Leu Thr Leu Cys Ser     3095 3100 3105 Phe Ile Ser Ala Leu Gly Val Asp Ile Ile Ala Gln Val Glu Ala     3110 3115 3120 Lys Asp Phe Gly Ala Glu Ser Lys Val Ser Val Asp Asp Leu Cys     3125 3130 3135 Lys Lys Ala Val Glu His Asn Ile Gln Ile Gly Lys Phe Ser Gln     3140 3145 3150 Leu Val Met Asn Arg Ala Thr Val Leu Ala Ser Ser Tyr Asp Thr     3155 3160 3165 Ala Trp Lys Lys His Asp Leu Val Arg Arg Leu Glu Thr Ser Ile     3170 3175 3180 Ser Ser Cys Lys Thr Ser Leu Gln Arg Val Gln Leu His Ile Ala     3185 3190 3195 Met Phe Gln Trp Gln His Glu Asp Leu Leu Ile Asn Arg Pro Gln     3200 3205 3210 Ala Met Ser Val Thr Pro Pro Pro Arg Ser Ala Ile Leu Thr Ser     3215 3220 3225 Met Lys Lys Lys Leu His Thr Leu Ser Gln Ile Glu Thr Ser Ile     3230 3235 3240 Ala Thr Val Gln Glu Lys Leu Ala Ala Leu Glu Ser Ser Ile Glu     3245 3250 3255 Gln Arg Leu Lys Trp Ala Gly Gly Ala Asn Pro Ala Leu Ala Pro     3260 3265 3270 Val Leu Gln Asp Phe Glu Ala Thr Ile Ala Glu Arg Arg Asn Leu     3275 3280 3285 Val Leu Lys Glu Ser Gln Arg Ala Ser Gln Val Thr Phe Leu Cys     3290 3295 3300 Ser Asn Ile Ile His Phe Glu Ser Leu Arg Thr Arg Thr Ala Glu     3305 3310 3315 Ala Leu Asn Leu Asp Ala Leu Phe Glu Leu Ile Lys Arg Cys     3320 3325 3330 Gln Gln Met Cys Ser Phe Ala Ser Gln Phe Asn Ser Ser Val Ser     3335 3340 3345 Glu Leu Glu Leu Arg Leu Leu Glu Arg Val Asp Thr Gly Leu Glu     3350 3355 3360 His Pro Ile Gly Ser Ser Glu Trp Leu Leu Ser Ala His Lys Gln     3365 3370 3375 Leu Thr Gln Asp Met Ser Thr Gln Arg Ala Ile Gln Thr Glu Lys     3380 3385 3390 Glu Gln Gln Ile Glu Thr Val Cys Glu Thr Ile Gln Asn Leu Val     3395 3400 3405 Asp Asn Ile Lys Thr Val Leu Thr Gly His Asn Arg Gln Leu Gly     3410 3415 3420 Asp Val Lys His Leu Leu Lys Ala Met Ala Lys Asp Glu Glu Ala     3425 3430 3435 Ala Leu Ala Asp Gly Glu Asp Val Pro Tyr Glu Asn Ser Val Arg     3440 3445 3450 Gln Phe Leu Gly Glu Tyr Lys Ser Trp Gln Asp Asn Ile Gln Thr     3455 3460 3465 Val Leu Phe Thr Leu Val Gln Ala Met Gly Gln Val Arg Ser Gln     3470 3475 3480 Glu His Val Glu Met Leu Gln Glu Ile Thr Pro Thr Leu Lys Glu     3485 3490 3495 Leu Lys Thr Gln Ser Gln Ser Ile Tyr Asn Asn Leu Val Ser Phe     3500 3505 3510 Ala Ser Pro Leu Val Thr Asp Ala Thr Asn Glu Cys Ser Ser Pro     3515 3520 3525 Thr Ser Ala Thr Tyr Gln Pro Ser Phe Ala Ala Ala Val Arg     3530 3535 3540 Ser Asn Thr Gly Gln Lys Thr Gln Pro Asp Val Met Ser Gln Asn     3545 3550 3555 Ala Arg Lys Leu Ile Gln Lys Asn Leu Ala Thr Ser Ala Asp Thr     3560 3565 3570 Pro Pro Ser Thr Val Pro Gly Thr Gly Lys Ser Val Ala Cys Ser     3575 3580 3585 Pro Lys Lys Ala Val Arg Asp Pro Lys Thr Gly Lys Ala Val Gln     3590 3595 3600 Glu Arg Asn Ser Tyr Ala Val Ser Val Trp Lys Arg Val Lys Ala     3605 3610 3615 Lys Leu Glu Gly Arg Asp Val Asp Pro Asn Arg Arg Met Ser Val     3620 3625 3630 Ala Glu Gln Val Asp Tyr Val Ile Lys Glu Ala Thr Asn Leu Asp     3635 3640 3645 Asn Leu Ala Gln Leu Tyr Glu Gly Trp Thr Ala Trp Val     3650 3655 3660 <210> 2 <211> 16065 <212> DNA <213> Homo sapiens <400> 2 gccgtgtgag cgtgaggagc tgccgccacc gcctgctcct cgtcgtcctc gtcctccggg 60 gccccggcga cgtgggccgc gcacggccct ggaaaagacg tcgcctcccc ttcatccgcc 120 tctctctcac cgcgccgctc ccgcctcctc gtcctgcgct gcgggctcag gcggaacccg 180 gaacggccgt cctcttcccc cgccctccgc cgcctcctcc ttctcctcct cctcctcctc 240 ctcctccttc tcggcttcct cctcagcccc gggccggagc ggggtgtcgg cggcggccgg 300 ttcgggcggc gactcgcgct tctttgggcg gcggcgcttg gccatgtcgt gtcggggaag 360 gtaatgagcc gcagagcccc ggggtctcgg ctgagcagcg gcggcggcgg cggcggcacc 420 aagtatccgc ggagctggaa tgactggcaa cccagaactg atagtgcatc agccgaccca 480 gataatttaa aatattcttc atccagagat agaggtggtt cttcctctta tggactgcaa 540 ccttcaaatt cagctgtggt gtctcggcaa aggcacgatg ataccagagt ccacgctgac 600 atacagaatg acgaaaaggg tggctacagt gtcaatggag gatctgggga aaatacttat 660 ggtcggaagt cgttggggca agagctgagg gttaacaatg tgaccagccc tgagttcacc 720 agtgttcagc atggcagtcg tgctttagcc accaaagaca tgaggaaatc acaggagaga 780 tcgatgtctt attctgatga gtctcgactg tcgaatcttc ttcggaggat cacccgggaa 840 gacgacagag accgaagatt ggctactgta aagcagttga aagaatttat tcagcaacca 900 gaaaataagc tggtactagt taaacaattg gataatatct tggctgctgt acatgacgtg 960 cttaatgaaa gtagcaaatt gcttcaggag ttgagacagg agggagcttg ctgtcttggc 1020 cttctttgtg cttctctgag ctatgaggct gagaagatct tcaagtggat ttttagcaaa 1080 tttagctcat ctgcaaaaga tgaagttaaa ctcctctact tatgtgccac ctacaaagca 1140 ctagagactg taggagaaaa gaaagccttt tcatctgtaa tgcagcttgt aatgaccagc 1200 ctgcagtcta ttcttgaaaa tgtggataca ccagaattgc tttgtaaatg tgttaagtgc 1260 attcttttgg tggctcgatg ttaccctcat attttcagca ctaattttag ggatacagtt 1320 gatatattag ttggatggca tatagatcat actcagaaac cttcgctcac gcagcaggta 1380 tctgggtggt tgcagagttt ggagccattt tgggtagctg atcttgcatt ttctactact 1440 cttcttggtc agtttctgga agacatggaa gcatatgctg aggacctcag ccatgtggcc 1500 tctggggaat cagtggatga agatgtccct cctccatcag tgtcattacc aaagctggct 1560 gcacttctcc gggtatttag tactgtggtg aggagcattg gggaacgctt cagcccaatt 1620 cggggtcctc caattactga ggcatatgta acagatgttc tgtacagagt aatgagatgt 1680 gtgacggctg caaaccaggt gtttttttct gaggctgtgt tgacagctgc taatgagtgt 1740 gttggtgttt tgctcggcag cttggatcct agcatgacta tacattgtga catggtcatt 1800 acatatggat tagaccaact ggagaattgc cagacttgtg gtaccgatta tatcatctca 1860 gtcttgaatt tactcacgct gattgttgaa cagataaata cgaaactgcc atcatcattt 1920 gtagaaaaac tgtttatacc atcatctaaa ctactattct tgcgttatca taaagaaaaa 1980 gaggttgttg ctgtagccca tgctgtttat caagcagtgc tcagcttgaa gaatattcct 2040 gtttggaga ctgcctataa gttaatattg ggagaaatga cttgtgccct aaacaacctc 2100 ctacacagtc tacaacttcc tgaggcctgt tctgaaataa aacatgaggc ttttaagaat 2160 catgtgttca atgtagacaa tgcaaaattt gtagttatat ttgacctcag tgccctgact 2220 acaattggaa atgccaaaaa ctcactaata gggatgtggg cgctatctcc aactgtcttt 2280 gcacttctga gtaagaatct gatgattgtg cacagtgacc tggctgttca cttccctgcc 2340 attcagtatg ctgtgctcta cacattgtat tctcattgta ccaggcatga tcactttatc 2400 tctagtagcc tcagttcttc ctctccttct ttgtttgatg gagctgtgat tagcactgta 2460 actacggcta caaagaaaca tttctcaatt atattaaatc ttctgggaat attacttaag 2520 aaagataacc ttaaccagga cacgaggaaa ctgttaatga cttgggcttt ggaagcagct 2580 gttttaatga agaagtctga aacatacgca cctttattct ctcttccgtc tttccataaa 2640 ttttgcaaag gccttttagc caacactctc gttgaagatg tgaatatctg tctgcaggca 2700 tgcagcagtc tacatgctct gtcctcttcc ttgccagatg atcttttaca gagatgtgtc 2760 gatgtttgcc gtgttcaact agtgcacagt ggaactcgta ttcgacaagc atttggaaaa 2820 ctgttgaaat caattccttt agatgttgtc ctaagcaata acaatcacac agaaattcaa 2880 gaaatttctt tagcattaag aagtcacatg agtaaagcac caagtaatac attccacccc 2940 caagatttct ctgatgttat tagttttatt ttgtatggga actctcatag aacagggaag 3000 gacaattggt tggaaagact gttctatagc tgccagagac tggataagcg tgaccagtca 3060 acaattccac gcaatctcct gaagacagat gctgtccttt ggcagtgggc catatgggaa 3120 gctgcacaat tcactgttct ttctaagctg agaaccccac tgggcagagc tcaagacacc 3180 ttccagacaa ttgaaggtat cattcgaagt ctcgcagctc acacattaaa ccctgatcag 3240 gatgttagtc agtggacaac tgcagacaat gatgaaggcc atggtaacaa ccaacttaga 3300 cttgttcttc ttctgcagta tctggaaaat ctggagaaat taatgtataa tgcatacgag 3360 ggatgtgcta atgcattaac ttcacctccc aaggtcatta gaactttttt ctataccaat 3420 cgccaaactt gtcaggactg gctaacgcgg attcgactct ccatcatgag ggtaggattg 3480 ttggcaggcc agcctgcagt gacagtgaga catggctttg acttgcttac agagatgaaa 3540 acaaccagcc tatctcaggg gaatgaattg gaagtaacca ttatgatggt ggtagaagca 3600 ttatgtgaac ttcattgtcc tgaagctata cagggaattg ctgtctggtc atcatctatt 3660 gttggaaaaa atcttctgtg gattaactca gtggctcaac aggctgaagg gaggtttgaa 3720 aaggcctctg tggagtacca ggaacacctg tgtgccatga caggtgttga ttgctgcatc 3780 tccagctttg acaaatcggt gctcacctta gccaatgctg ggcgtaacag tgccagcccg 3840 aaacattctc tgaatggtga atccagaaaa actgtgctgt ccaaaccgac tgactcttcc 3900 cctgaggtta taaattattt aggaaataaa gcatgtgagt gctacatctc aattgccgat 3960 tgggctgctg tgcaggaatg gcagaacgct atccatgact tgaaaaagag taccagtagc 4020 acttccctca acctgaaagc tgacttcaac tatataaaat cattaagcag ctttgagtct 4080 ggaaaatttg ttgaatgtac cgagcagtta gaattgttac caggagaaaa tatcaatcta 4140 cttgctggag gatcaaaaga aaaaatagac atgaaaaaac tgcttcctaa catgttaagt 4200 ccggatccga gggaacttca gaaatccatt gaagttcaat tgttaagaag ttctgtttgt 4260 ttggcaactg ctttaaaccc gatagaacaa gatcagaagt ggcagtctat aactgaaaat 4320 gtggtaaagt acttgaagca aacatcccgc atcgctattg gacctctgag actttctact 4380 ttaacagttt cacagtcttt gccagttcta agtaccttgc agctgtattg ctcatctgct 4440 ttggagaaca cagtttctaa cagactttca acagaggact gtcttattcc actcttcagt 4500 gaagctttac gttcatgtaa acagcatgac gtgaggccat ggatgcaggc attaaggtat 4560 actatgtacc agaatcagtt gttggagaaa attaaagaac aaacagtccc aattagaagc 4620 catctcatgg aattaggtct aacagcagca aaatttgcta gaaaacgagg gaatgtgtcc 4680 cttgcaacaa gactgctggc acagtgcagt gaagttcagc tgggaaagac caccactgca 4740 caggatttag tccaacattt taaaaaacta tcaacccaag gtcaagtgga tgaaaaatgg 4800 gt; gcaatggaaa tgttgagttc ttgtgccata tctttctgca agtctgtgaa agctgaatat 4920 gcagttgcta aatcaattct gacactggct aaatggatcc aggcagaatg gaaagagatt 4980 tcaggacagc tgaaacaggt ttacagagct cagcaccaac agaacttcac aggtctttct 5040 actttgtcta aaaacatact cactctaata gaactgccat ctgttaatac gatggaagaa 5100 gagtatcctc ggatcgagag tgaatctaca gtgcatattg gagttggaga acctgacttc 5160 attttgggac agttgtatca cctgtcttca gtacaggcac ctgaagtagc caaatcttgg 5220 gcagcgttgg ccagctgggc ttataggtgg ggcagaaagg tggttgacaa tgccagtcag 5280 ggagaaggtg ttcgtctgct gcctagagaa aaatctgaag ttcagaatct acttccagac 5340 actataactg aggaagagaa agagagaata tatggtattc ttggacaggc tgtgtgtcgg 5400 ccggcgggga ttcaggatga agatataaca cttcagataa ctgagagtga agacaacgaa 5460 gaagatgaca tggttgatgt tatctggcgt cagttgatat caagctgccc atggctttca 5520 gaacttgatg aaagtgcaac tgaaggagtt attaaagtgt ggaggaaagt tgtagataga 5580 atattcagcc tgtacaaact ctcttgcagt gcatacttta ctttccttaa actcaacgct 5640 ggtcaaattc ctttagatga ggatgaccct aggctgcatt taagtcacag agtggaacag 5700 agcactgatg acatgattgt gatggccaca ttgcgcctgc tgcggttgct cgtgaagcat 5760 gctggtgagc ttcggcagta tctggagcac ggcttggaga caacacccac tgcaccatgg 5820 agaggaatta ttccgcaact tttctcacgc ttaaaccacc ctgaagtgta tgtgcgccaa 5880 agtatttgta accttctctg ccgtgtggct caagattccc cacatctcat attgtatcct 5940 gcaatagtgg gtaccatatc gcttagtagt gaatcccagg cttcaggaaa taaattttcc 6000 actgcaattc caactttact tggcaatatt caaggagaag aattgctggt ttctgaatgt 6060 gagggaggaa gtcctcctgc atctcaggat agcaataagg atgaacctaa aagtggatta 6120 aatgaagacc aagccatgat gcaggattgt tacagcaaaa ttgtagataa gctgtcctct 6180 gcaaacccca ccatggtatt acaggttcag atgctcgtgg ctgaactgcg cagggtcact 6240 gtgctctggg atgagctctg gctgggagtt ttgctgcaac aacacatgta tgtcctgaga 6300 cgaattcagc agcttgaaga tgaggtgaag agagtccaga acaacaacac cttacgcaaa 6360 gaagagaaaa ttgcaatcat gagggagaag cacacagctt tgatgaagcc catcgtattt 6420 gctttggagc atgtgaggag tatcacagcg gctcctgcag aaacacctca tgaaaaatgg 6480 tttcaggata actatggtga tgccattgaa aatgccctag aaaaactgaa gactccattg 6540 aaccctgcaa agcctgggag cagctggatt ccatttaaag agataatgct aagtttgcaa 6600 cagagagcac agaaacgtgc aagttacatc ttgcgtcttg aagaaatcag tccatggttg 6660 gctgccatga ctaacactga aattgctctt cctggggaag tctcagccag agacactgtc 6720 acaatccata gtgtgggcgg aaccatcaca atcttaccga ctaaaaccaa gccaaagaaa 6780 cttctctttc ttggatcaga tgggaagagc tatccttatc ttttcaaagg actggaggat 6840 ttacatctgg atgagagaat aatgcagttc ctatctattg tgaataccat gtttgctaca 6900 attaatcgcc aagaaacacc ccggttccat gctcgacact attctgtaac accactagga 6960 acaagatcag gactaatcca gtgggtagat ggagccacac ccttatttgg tctttacaaa 7020 cgatggcaac aacgggaagc tgccttacaa gcacaaaagg cccaagattc ctaccaaact 7080 cctcagaatc ctggaattgt accccgtcct agtgaacttt attacagtaa aattggccct 7140 gctttgaaaa cagttgggct tagcctggat gtgtcccgtc gggattggcc tcttcatgta 7200 atgaaggcag tattggaaga gttaatggag gccacacccc cgaatctcct tgccaaagag 7260 ctctggtcat cttgcacaac acctgatgaa tggtggagag ttacgcagtc ttatgcaaga 7320 tctactgcag tcatgtctat ggttggatac ataattggcc ttggagacag acatctggat 7380 aatgttctta tagatatgac gactggagaa gttgttcaca tagattacaa tgtttgcttt 7440 gaaaaaggta aaagccttag agttcctgag aaagtacctt ttcgaatgac acaaaacatt 7500 gaaacagcac tgggtgtaac tggagtagaa ggtgtattta ggctttcatg tgagcaggtt 7560 ttacacatta tgcggcgtgg cagagagacc ctgctgacgc tgctggaggc ctttgtgtac 7620 gaccctctgg tggactggac agcaggaggc gaggctgggt ttgctggtgc tgtctatggt 7680 ggaggtggcc agcaggccga gagcaagcag agcaagagag agatggagcg agagatcacc 7740 cgcagcctgt tttcttctag agtagctgag attaaggtga actggtttaa gaatagagat 7800 gagatgctgg ttgtgcttcc caagttggac ggtagcttag atgaatacct aagcttgcaa 7860 gagcaactga cagatgtgga aaaactgcag ggcaaactac tggaggaaat agagtttcta 7920 gaaggagctg aaggggtgga tcatccttct catactctgc aacacaggta ttctgagcac 7980 acccaactac agactcagca aagagctgtt caggaagcaa tccaggtgaa gctgaatgaa 8040 tttgaacaat ggataacaca ttatcaggct gcattcaata atttagaagc aacacagctt 8100 gcaagcttgc ttcaagagat aagcacacaa atggaccttg gtcctccaag ttacgtgcca 8160 gcaacagcct ttctgcagaa tgctggtcag gcccacttga ttagccagtg cgagcagctg 8220 gagggggagg ttggtgctct cctgcagcag aggcgctccg tgctccgtgg ctgtctggag 8280 caactgcatc actatgcaac cgtggccctg cagtatccga aggccatatt tcagaaacat 8340 cgaattgaac agtggaagac ctggatggaa gagctcatct gtaacaccac agtagagcgt 8400 tgtcaagagc tctataggaa atatgaaatg caatatgctc cccagccacc cccaacagtg 8460 tgtcagttca tcactgccac tgaaatgacc ctgcagcgat acgcagcaga catcaacagc 8520 agacttatta gacaagtgga acgcttgaaa caggaagctg tcactgtgcc agtttgtgaa 8580 gatcagttga aagaaattga acgttgcatt aaagttttcc ttcatgagaa tggagaagaa 8640 ggatctttga gtctagcaag tgttattatt tctgcccttt gtacccttac aaggcgtaac 8700 ctgatgatgg aaggtgcagc gtcaagtgct ggagaacagc tggttgatct gacttctcgg 8760 gatggagcct ggttcttgga ggaactctgc agtatgagcg gaaacgtcac ctgcttggtt 8820 cagttactga agcagtgcca cctggtgcca caggacttag atatcccgaa ccccatggaa 8880 gcgtctgaga cagttcactt agccaatgga gtgtatacct cacttcagga attgaattcg 8940 aattcggc aaatcatatt tccagaagca cttcgatgtt taatgaaagg ggaatacacg 9000 ttagaaagta tgctgcatga actggacggt cttattgagc agaccaccga tggcgttccc 9060 ctgcagactc tagtggaatc tcttcaggcc tacttaagaa acgcagctat gggactggaa 9120 gaagaaacac atgctcatta catcgatgtt gccagactac tacatgctca gtacggtgaa 9180 ttaatccaac cgagaaatgg ttcagttgat gaaacaccca aaatgtcagc tggccagatg 9240 cttttggtag cattcgatgg catgtttgct caagttgaaa ctgctttcag cttattagtt 9300 gaaaagttga acaagatgga aattcccata gcttggcgaa agattgacat cataagggaa 9360 gccaggagta ctcaagttaa tttttttgat gatgataatc accggcaggt gctagaagag 9420 attttctttc taaaaagact acagactatt aaggagttct tcaggctctg tggtaccttt 9480 tctaaaacat tgtcaggatc aagttcactt gaagatcaga atactgtgaa tgggcctgta 9540 cagattgtca atgtgaaaac cctttttaga aactcttgtt tcagtgaaga ccaaatggcc 9600 aaacctatca aggcattcac agctgacttt gtgaggcagc tcttgatagg gctacccaac 9660 caagccctcg gactcacact gtgcagtttt atcagtgctc tgggtgtaga catcattgct 9720 caagtagagg caaaggactt tggtgccgaa agcaaagttt ctgttgatga tctctgtaag 9780 aaagcggtgg aacataacat ccagataggg aagttctctc agctggttat gaacagggca 9840 actgtgttag caagttctta cgacactgcc tggaagaagc atgacttggt gcgaaggcta 9900 gaaaccagta tttcttcttg taagacaagc ctgcagcggg ttcagctgca tattgccatg 9960 tttcagtggc aacatgaaga tctacttatc aatagaccac aagccatgtc agtcacacct 10020 cccccacggt ctgctatcct aaccagcatg aaaaagaagc tgcataccct gagccagatt 10080 gaaacttcta ttgcaacagt tcaggagaag ctagctgcac ttgaatcaag tattgaacag 10140 cgactcaagt gggcaggtgg tgccaaccct gcattggccc ctgtactaca agattttgaa 10200 gcaacgatag ctgaaagaag aaatcttgtc cttaaagaga gccaaagagc aagtcaggtc 10260 acatttctct gcagcaatat cattcatttt gaaagtttac gaacaagaac tgcagaagcc 10320 ttaaacctgg atgcggcgtt atttgaacta atcaagcgat gtcagcagat gtgttcgttt 10380 gcatcacagt ttaacagttc agtgtctgag ttagagcttc gtttattaca gagagtggac 10440 actggtcttg aacatcctat tggcagctct gaatggcttt tgtcagcaca caaacagttg 10500 acccaggata tgtctactca gagggcaatt cagacagaga aagagcagca gatagaaacg 10560 gtctgtgaaa caattcagaa tctggttgat aatataaaga ctgtgctcac tggtcataac 10620 cgacagcttg gagatgtcaa acatctcttg aaagctatgg ctaaggatga agaagctgct 10680 ctggcagatg gtgaagatgt tccctatgag aacagtgtta ggcagttttt gggtgaatat 10740 aaatcatggc aagacaacat tcaaacagtt ctatttacat tagtccaggc tatgggtcag 10800 gttcgaagtc aagaacacgt tgaaatgctc caggaaatca ctcccacctt gaaagaactg 10860 aaaacacaaa gtcagagtat ctataataat ttagtgagtt ttgcatcacc cttagtcacc 10920 gatgcaacaa atgaatgttc gagtccaacg tcatctgcta cttatcagcc atccttcgct 10980 gcagcagtcc ggagtaacac tggccagaag actcagcctg atgtcatgtc acagaatgct 11040 agaaagctga tccagaaaaa tcttgctaca tcagctgata ctccaccaag caccgttcca 11100 ggaactggca agagtgttgc ttgtagtcct aaaaaggcag tcagagaccc taaaactggg 11160 aaagcggtgc aagagagaaa ctcctatgca gtgagtgtgt ggaagagagt gaaagccaag 11220 ttagagggcc gagatgttga tccgaatagg aggatgtcag ttgctgaaca ggttgactat 11280 gtcattaagg aagcaactaa tctagataac ttggctcagc tgtatgaagg ttggacagcc 11340 tgggtgtgaa tggcaagaca gtagatgagt ctggttaagc gaggtcagac atccacca 11400 atcaactcag cctcaggcat ccaaagccac accacagtcg gtggtgatgc aactgggggc 11460 ttactctgag gaaacctagg aaatctcggt gcactaggaa gtgaatcccg caggacagct 11520 gcactcaggg atacgcccaa caccatggcc tgcaacccca gggtcaaggg tgaaggaaag 11580 caagctcacc gcctgaacac ggagattgtc tttctgccac agaacagcag cagacgtgtc 11640 gggaggttag ctgcggaaag aaatcgggat gccgcggagc acagagtgat ttggaactcc 11700 attccacctg accctgtgtg tacaatccag gaaaaaaaca aaccccactc agaaacagag 11760 aaaactgggg tcgcgaagaa atcacagcca aggaagattt gatgcattca gattctcgtg 11820 taacacttgt tgcttggcaa cagtactggt tgggttgacc agtaagtaga aaaaggctaa 11880 aggctatgcg atatgaattt cagaaatgga ctgaaaatgg agagctatgt aacagataca 11940 ctacagtaga agaacttact tctgaaatga agggaaaaaa accaccccat cgttccctac 12000 tcctccccac cacttacccg ttcccccttt acctaatcta gtagattagc catctttcaa 12060 attcactttt atttcagtcc ttatatttca tatacttccg tctcgatgct gttaacaact 12120 tctgataaca tggaaaattc aaggattgtt taaaggtctg atgatcacac acaaaatgta 12180 attccggtta tttaagtcat ttctgtgatt ctatcatgta cagtttccag aattgtcact 12240 gtgcattcaa aagtaatgaa tctaacagac atttgattta atgtacactc ccttttgctt 12300 atagtgtgca ttttttttgg aggtcattca aattttccct cttctgtgat agctgtagtt 12360 tctttcatag aaagtagcta atccagtgta atcttttacc tttttaaaaa ccaagataga 12420 gtatctatta gagttttaca ttgttgatga tagattaaca ataaagtgat gttctggtgg 12480 aggtagactg aaattttttt aattcatgtt tttcatttga tacttttaat ttacacttag 12540 taaattaaaa gttgtttaat ttacttggca ttttaggaca tgtacatgaa acagtgaaaa 12600 tgagatccac caacatcttt tattaagttc agttattagt ctgtgaagtg ctttactttt 12660 tgcacaattt taatagcttg ctattcagta atacattata gtgaattcat gatcaaggtt 12720 tccttaaatt tagcattgca tttcagtact gactgtgtaa gctaaattgc tgatccaaaa 12780 taaaaaccca gactagaata gggttcttaa aatcaagtat caatacaaaa tagaacacaa 12840 ttaaaatctt aattgttggc tgggcacagt ggctcacgcc tgtaatccca gcactttggg 12900 aggccgaggc gggcggatca tgaggttagg agagcgagac catcctggct aacacggtga 12960 aaccccgtct ttactaaaaa tacaaaaaaa attagccggg cgtggtggcg ggcgcctgta 13020 gtcccagcta ctcgggaggc tgaggcagga gaatggcgtg aacccaggag gcggagcttg 13080 cagtgagccg agattgtgcc actgcactcc agcctgggca acagagctag actctgtgtc 13140 aaaaataaat gactagataa aaaaaaaaat tgtttgagta cattttccct gcattttaga 13200 gattaggaca gtggtcactt tctagttgcc gtcttcacag acaaacttga aaggtattaa 13260 ggaaaaaatt ccacatagct ctgggccttt tttgtattct gattgccacg ttaatctgta 13320 atcgttaagt acccatgaaa gaatgtgttt cagtatcagt gcttttttgg tactttaaca 13380 agtattgtag gcacggtgga tttttttgaa atacccatgt gtccaatagc aagttaagga 13440 acctagcgca tcaaattttg ttttcttcat tcatttggaa ccttattttc gcaaaaaacc 13500 tagctggaat aataatgcca tattgtattt tgcacactgc tttattttct agaggctctg 13560 ggagcaaatt acattcatca cattacctct gctctctcaa gattaaagtc tttcagcaac 13620 attctttatt gtcatcataa ggaaaaactt ttatcgcaat gatagtcagt tcacattagt 13680 ttagcactat agatagtatt cagaaattgc tttctctttg gtaaagaaga taaataggtg 13740 aattttattg cctgtgtttt caggcttcag aggtacctgg caccttactc aagcaaaaac 13800 aaaaaacagc tttacttcaa aagcatgtgc ctctggtaaa ttatccatca cttttgtttt 13860 aaagtggtcc ctccaagaat aatgtggcat acacagtggg tttggttgta aggcagatgt 13920 aatagatgac ttcaaaagcc tgctccttac tgcactctgg acaaggccct ggtctgtata 13980 gtttggcttc ctctgttaag tcattctaca aggtgacttg ccatttgaac tttcgtaaga 14040 gacctcagca gttagactga gaaaagttag agtgctgtag ttatgaagtc atacattttt 14100 gataaaatac ctgtggaaaa ccagggatcc tctcctgttt ctctctcttg cctccccctt 14160 tccctccatt cctctgtcgc ctccccctct cctccacttt ctttaagaat cagggggtac 14220 agaataacct acaaacaacc tcttcaaagt acccttggaa attgaagttc aatcttaagt 14280 tttttgctgt ctttaattta ctagaattgc ctaattttta gttgatttct ctacagagct 14340 tagcttgtgt agttatttct cttttactgt tgctttggtg tgtcttgaag tttgattgat 14400 tatttttggt cattgagttc ttagtgtagt ttgctagatg attattaaga ttcttttgtg 14460 tctgacactt gtggtgagtt gcttttgaaa tctgttgaga tttccatgtg agaactgata 14520 atcaggctct tgatctgctt ccctaaatta cttttttaga gcccaaaccc caggtttagg 14580 gtgagggttt gtaatacaaa gaaacacttc catcacttct gcccttaacc cttgcctcta 14640 ttacctaagc ttagtaagta gttttcttaa tattgtccaa tgtttggtgt tatctgcatt 14700 gttttttgtt tttttaattg tggttgttct gacgtgtgaa atttaaggaa agagccattt 14760 tttaaaaatg ccgagcaggg caatgcaagt acagccaaat attagacttg atgtgcaatc 14820 ttcggtcctt tttaatctgg ggtattatag gcagtacttt aaattgcaaa gtcttccggg 14880 cctattttcc tctacatttt tgtaattaac tctgggggct tacttgtttt ggcagtactg 14940 aaatcaaagg agctggttct tcttttctcc caattatttt catatgaaag cacctacaat 15000 tagcctgtta gtcctattca gatacatcaa atatcagtga atgctttact attcgcacat 15060 ttaagcatct ttgttttaca taaaattaga gtatgaaaac cagtgttcaa ttttttatct 15120 tgttgagctt gtaaaatgcc agcaatttaa aactaggact tttcccccca taagccaagg 15180 aggtagaatt actaatacaa gggttaaaga aggtagattt tgttttcaat atttgggtaa 15240 tattagaaag attcttccca cagggaagaa ctagcaagtg tcccaatttt ttccaaacgt 15300 gt; ttaggcctgg ataacagtat caccatcctt atttacagaa gggtaaaact gactcttaat 15420 gagaaaagct ttataagttc aagggctgta aaatatgaac tacttagggt cgtttgcctt 15480 ccatgggaac ttggctagac ttagaaaaag ctgtttgttg tgctaatgta aaagtgtcat 15540 acaatttaga agatttttga agatggtaaa cttagaagaa ttctatgttc tgaaatgcac 15600 acttttagaa tgtttttctt tgaaaacagg ctaatagttt tttctttttt tgacaaagtt 15660 tcagctcctc tttaaagtta ttgtgtcatt tttctggttt aaatttccct tatatttcca 15720 cctgtaatgt cagtggcaac aacatcatac ttcacttact tgttaattta ctttttaccc 15780 ttattctaag agcaagttga gttgaactga atcttccttg tcttagtaac aatgtataaa 15840 tagtggcttt tctgtacaaa aggttgtaat gcctcctgat ggatataatt ttgtgattgt 15900 atttaaaagt tgaataaatc acaccagctt cctgaaaatg ttcataatgc atcttttgga 15960 aaacaaatac atgcctactt tgtgcatatt tgcattaaca tggcaaagat tgtatgaaat 16020 acctgttttt cagaaaataa aggttcagtc tcaaaagata cagca 16065

Claims (13)

A composition for enhancing the sensitivity of an anticancer agent comprising SMG-1 (Suppressor of Morphogenesis in Genitalia-1) as an active ingredient. The method according to claim 1,
Wherein the anticancer agent is sorafenib. The method according to claim 1,
Wherein the SMG-1 has the amino acid sequence of SEQ ID NO: 1. The method according to claim 1,
Wherein the composition is capable of being administered simultaneously, separately or sequentially with an anti-cancer agent. The method according to claim 1,
Wherein the cancer is selected from the group consisting of lung cancer, stomach cancer, colon cancer, liver cancer, osteocarcinoma, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectum cancer, , Cancer of the uterine cervix, vaginal cancer, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma Wherein the cancer is one or more solid tumors selected from the group consisting of bladder cancer, kidney or urothelial cancer, kidney cell carcinoma, renal pelvic carcinoma, CNS tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma, pituitary adenoma / RTI &gt; 3. The method of claim 2,
Wherein the cancer is liver cancer. An anticancer composition comprising an anticancer agent and SMG-1 (Suppressor of Morphogenesis in Genitalia-1) as an active ingredient. 8. The method of claim 7,
Wherein the anticancer agent is sorafenib. 8. The method of claim 7,
Wherein the SMG-1 has the amino acid sequence of SEQ ID NO: 1. 8. The method of claim 7,
Wherein the cancer is selected from the group consisting of lung cancer, stomach cancer, colon cancer, liver cancer, osteocarcinoma, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectum cancer, , Cancer of the uterine cervix, vaginal cancer, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma Wherein the composition is at least one kind of solid cancer selected from the group consisting of bladder cancer, kidney or urothelial cancer, kidney cell carcinoma, kidney pelvic carcinoma, CNS tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma, pituitary adenoma . A composition for promoting sensitivity to an anticancer agent comprising an expression vector comprising a polynucleotide encoding SMG-1 (Suppressor of Morphogenesis in Genitalia-1) as an active ingredient. 12. The method of claim 11,
Wherein the polynucleotide has the nucleotide sequence of SEQ ID NO: 2. 12. The method of claim 11,
Wherein the anticancer agent is sorafenib.

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