KR20180045650A - Pharmaceutical composition for preventing or treating ovarian cancer - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating ovarian cancer, and more particularly, to a pharmaceutical composition capable of preventing or treating cancers, especially ovarian cancer using E47 protein. The E47 protein is represented by an amino acid sequence of SEQ ID NO: 1.

Description

[0001] The present invention relates to a pharmaceutical composition for preventing or treating ovarian cancer,

The present invention relates to a pharmaceutical composition for preventing or treating ovarian cancer, and more particularly, to a pharmaceutical composition capable of preventing or treating ovarian cancer in cancer by using E47 protein.

Cancer is one of the most common causes of death worldwide. Approximately 10 million new cases occur each year, accounting for approximately 12% of all deaths and the third leading cause of death.

Of the various types of cancer, ovarian cancer is the most fatal cancer of the female gynecologist, making it the fifth most common cause of female cancer deaths in the United States. Moreover, the onset is occurring in an industrialized country. Although there is epidemiologic evidence associated with impaired endocrine function, the etiology of tumorigenic transformation is unknown. The incidence of ovarian cancer is higher in women who do not have children and those who have early menopause. Because ovarian cancer is the second most common cancer in Korea, it is difficult to diagnose early due to lack of early symptoms and proper diagnostic markers. More than 70% of patients are found in advanced stage 3 or more, to be. Early detection is the best way to reduce mortality from ovarian cancer, and it is urgent to develop markers that can monitor treatment effects and therapeutic responses in chemotherapy.

Ovarian cancer can be divided into epithelial cell cancer, germ cell cancer and hepatocellular carcinoma depending on the cells constituting the cancer tissue, and it can be divided into mucinous ovarian cancer, serous ovarian cancer, And ovarian cancer.

E2A (transcription factor 3; TCF-3) is a class I bHLH transcription factor and splicing produces two proteins, E12 and E47. The E47 protein is homodimer ) To bind to DNA. The E12 protein binds to other bHLH proteins and binds to an "E-box" DNA sequence in a heterodimer state to regulate the expression of genes that regulate cell growth and differentiation.

One of the important roles of the E protein is to inhibit cell survival and cell cycle progression. In addition, E protein plays an important role in the development of lymphocytes. B-cell progenitors are pro-B cells, pre-B cells, immature B cells, (Immature B cell), virgin B cell (naive B cell), and active B cell (active B cell). It also contributes to the process of early thymic progenitor cell migration into the thymus and the differentiation of T cells.

It is an object of the present invention to provide a pharmaceutical composition which can effectively prevent the proliferation of ovarian cancer cells using the E47 protein and prevent and / or treat ovarian cancer.

Another object of the present invention is to provide a pharmaceutical composition for inhibiting metastasis of ovarian cancer which can inhibit metastasis of ovarian cancer cells using E47 protein.

However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.

As a result of the study, the inventors of the present invention have confirmed that the use of the E47 protein effectively inhibits the proliferation of ovarian cancer cells in cancer, thereby preventing or treating ovarian cancer, and further inhibiting the progression of ovarian cancer. .

Specifically, according to one embodiment of the present invention, there is provided a pharmaceutical composition for preventing or treating cancer comprising E47 protein as an active ingredient.

According to another embodiment of the present invention, there is provided a pharmaceutical composition for inhibiting invasion and metastasis of cancer comprising E47 protein as an active ingredient.

In the present invention, the E47 protein may be represented by the amino acid sequence of SEQ ID NO: 1.

In the present invention, the E47 protein is associated with a modified estrogen receptor and can not migrate into the nucleus. Therefore, the E47 protein may not be functionally activated because it remains in the cytoplasm. Accordingly, in the present invention, tamoxifen is used in combination with the E47 protein to bind the E47 protein-coupled modified estrogen receptor to induce the E47 protein into the nucleus to functionally activate the E47 protein.

In the present invention, the cancer to be prevented or treated may be at least one selected from the group consisting of ovarian cancer, uterine cancer, stomach cancer, brain cancer, rectal cancer, colon cancer, lung cancer, skin cancer, blood cancer and liver cancer, .

The pharmaceutical composition of the present invention may further be administered in combination with other anticancer drugs, thereby effectively treating cancer cells, and further, may be used as a pharmaceutical composition for inhibiting cancer recurrence.

Examples of the anticancer agent include nitrogene mustard, imatinib, oxaliplatin, rituximab, elotinib, neratinib, lapatinib, zetitib, bandetanib, nilotinib, semathanib, conservinib, acitinib, , Corticosteroids, cisplatin, cetuximab, bismuth alum, asparaginase, tretinoin, hydroxycarbamate, terephthalic acid, tretinoin, Amlodipine, amlodipine, amlodipine, amlodipine, amlodipine, amide, amlodipine, amlodipine, amlodipine, amlodipine, But are not limited to, chitosan, gemcitabine, doxifluridine, femetrexed, tegafur, capecitabine, gimeracin, oteracil, azacytidine, methotrexate, uracil, cytarabine, fluorouracil, Tabin, flutamide, The compounds of the present invention may be selected from the group consisting of cefcitabine, decitabine, mercaptopurine, thioguanine, cladribine, calmophor, ralitriptycde, docetaxel, paclitaxel, irinotecan, velotecan, topotecan, vinorelbine, etoposide, vinblastine, The compounds of the present invention may be used in combination with one or more of the following compounds: nephrin, mitomycin, bromomycin, dactinomycin, pyra rubicin, aclarubicin, pepromycin, temsirolimus, temozolomide, But are not limited to, corticosteroids such as corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, It is possible to use at least one selected from the group consisting of fenofibrate, tolomephen, testolactone, anastrozole, letrozole, borozol, bicalutamide, rosmutin, 5FU, borinostat, entinostate and carmustine. But is not limited to.

In the present invention, the pharmaceutical composition may be in the form of a capsule, a tablet, a granule, an injection, an ointment, a powder or a drink, and the pharmaceutical composition may be a human.

The pharmaceutical composition of the present invention may be formulated in the form of oral preparations such as powders, granules, capsules, tablets, aqueous suspensions, etc., external preparations, suppositories and sterilized injection solutions according to a conventional method, . The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be a binder, a lubricant, a disintegrant, an excipient, a solubilizing agent, a dispersing agent, a stabilizer, a suspending agent, a coloring matter, a perfume or the like in the case of oral administration. A solubilizing agent, an isotonic agent, a stabilizer and the like may be mixed and used. In the case of topical administration, a base, an excipient, a lubricant, a preservative and the like may be used. Formulations of the pharmaceutical compositions of the present invention may be prepared in a variety of ways by mixing with a pharmaceutically acceptable carrier as described above. For example, oral administration may be in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc. In the case of injections, they may be formulated in unit dosage ampoules or in multiple dosage forms have. Other, solutions, suspensions, tablets, capsules, sustained-release preparations and the like.

Examples of suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltoditol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil. Further, it may further include a filler, an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, an antiseptic, and the like.

The route of administration of the pharmaceutical composition according to the present invention may be, but is not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, , Sublingual or rectal. Oral or parenteral administration is preferred. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical compositions of the present invention may also be administered in the form of suppositories for rectal administration.

The pharmaceutical composition of the present invention may be administered orally or parenterally depending on various factors including the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, And the dose of the pharmaceutical composition may be appropriately selected by a person skilled in the art depending on the condition of the patient, the body weight, the degree of disease, the mode of administration, the route of administration and the period of time, and is preferably from 0.0001 to 50 mg / kg or 0.001 to 50 mg / kg. The administration may be carried out once a day or divided into several times. The dose is not intended to limit the scope of the invention in any way. The pharmaceutical composition according to the present invention can be formulated into pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions.

In the present invention, "prevention" means any action that inhibits cancer formation or delays onset of cancer by administration of a pharmaceutical composition, and "treatment" means that administration of a pharmaceutical composition improves or alleviates the symptoms of the disease It means all the actions that are changed.

As used herein, the term "cancer metastasis" refers to a condition in which malignant tumors have spread to other tissues away from organs that have developed. As a malignant tumor originating from one organs progresses, it spreads from other organs, such as the first primary site, to other tissues. Metastasis is a phenomenon associated with the progression of malignant tumors, which can occur when malignant tumor cells multiply and cancer progresses to acquire new genetic traits. Metastasis can occur when tumor cells that acquire new genetic traits enter the blood vessels and lymph nodes, circulate along the blood and lymph, and settle and proliferate in other tissues.

The pharmaceutical composition according to the present invention can effectively inhibit cancer cell proliferation not only to prevent and / or treat cancer, but also to effectively inhibit invasion or metastasis of cancer cells.

FIG. 1 is a graph showing the results of putative copy-number alterations by GISTIC from 570 ovarian serous cystadenocarcinoma patients obtained from TCGA data in Example 1. FIG.
FIGS. 2 (a) to 2 (d) show the results of analysis of the number of copies of ID genes and mRNA expression in 570 ovarian adenocarcinomas obtained from the TCGA data in Example 1. FIG.
FIGS. 3 (a) to 3 (d) show the results of analysis of the degree of methylation of the ID gene and mRNA expression in 570 ovarian adenocarcinomas obtained from the TCGA data in Example 1. FIG.
Fig. 4 (a) shows the results of analysis of the relationship between the number of copies of the E2A gene and mRNA expression in 570 ovarian adenocarcinomas obtained from the TCGA data in Example 1, and Fig. 4 (b) And mRNA expression was analyzed.
FIG. 5 (a) shows the result of analysis of the ID gene and E2A gene copy number of ovarian cancer stage in 570 ovarian adenocarcinoma patients obtained from TCGA data in Example 1, (b) Methylation analysis results.
Figure 6 compares mRNA expression changes of the ID gene and E2A gene in early ovarian cancer (stage 1) and advanced ovarian cancer (stage 3C, 4) in 570 ovarian adenocarcinomas obtained from TCGA data in Example 1 The results are shown.
FIG. 7 shows OncoPrint analysis of gene changes of IDs 1 to 4 in 570 ovarian adenocarcinomas obtained from TCGA data in Example 1. FIG.
8 (a) to 8 (d) show Kaplan-Meier evaluation of genetic change and overall survival time of IDs 1 to 4 in 570 ovarian adenocarcinomas obtained from TCGA data in Example 1. FIG.
9 is a graph showing changes in cancer cell growth using a 200-magnification microscope after 24, 48 and 72 hours after treatment of SKOV-3 / Luc cell line and SKOV-3 / Luc / E47 ^mer cell line in Example 2 with tamoxifen And the photographs observed.
FIG. 10 is a graph showing changes in cell number after 24, 48 and 72 hours after treatment of tamoxifen with the culture solution of SKOV-3 / Luc cell line and SKOV-3 / Luc / E47 ^mer cell line in Example 2, Respectively.
FIG. 11 is a graph showing changes in tumor size with time in a mouse model transplanted with SKOV-3 / Luc cell line and SKOV-3 / Luc / E47 ^mer cell line in Example 3. FIG.
FIG. 12 is a photograph of a tumor obtained from a mouse model transplanted with SKOV-3 / Luc cell line and SKOV-3 / Luc / E47 ^mer cell line in Example 3 by small animal optical image.
FIG. 13 is a graph showing the results of measurement of changes in cell number after 2, 4, 6 and 8 days after treatment with tamoxifen in the culture medium of cell line and cell line in Comparative Example 1. FIG.
FIG. 14 is a graph showing changes in tumor size with time in a mouse model in which a cell line and a cell line were transplanted in Comparative Example 2. FIG.

Hereinafter, the present invention will be described in more detail with reference to Examples. It will be apparent to those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example

[Example 1] Analysis of expression and expression of ID gene and E2A gene in ovarian cancer

The results of analyzing the degree of increase and decrease of the ID gene and the E2A gene copy number in TCGA data of ovarian cancer are shown in Table 1 and FIG. In detail, Table 1 below shows putative copy-number alterations by GISTIC in 570 ovarian serous cystadenocarcinoma patients obtained from TCGA data.

Number of gene copies * Gene (No,%) ID1 ID2 ID3 ID4 E2A -2 0 (0.0) 2 (0.4) 1 (0.2) 0 (0.0) 26 (4.6) -One 20 (3.5) 106 (18.6) 246 (43.2) 82 (14.4) 477 (83.7) 0 219 (38.4) 245 (43.0) 193 (33.9) 199 (34.9) 47 (8.2) One 289 (50.7) 195 (34.2) 118 (20.7) 223 (39.1) 18 (3.2) 2 42 (7.4) 22 (3.9) 12 (2.1) 66 (11.6) 2 (0.4)

* -2 = homozygous deletion; -1 = hemizygous deletion; 0 = neutral / no change; 1 = gain; 2 = high level amplification

According to Table 1 and FIG. 1, the ID-1 gene was increased in 58.1% and decreased only in 3.5% in ovarian cancer patients, and the ID-2 gene was increased in 38.1% and decreased in 18.9%. In addition, ID-3 gene was increased in 22.8% and decreased in 43.3%, ID-4 gene was increased in 50.7% and decreased in 14.4%. On the other hand, the E2A gene had a gene copy number loss in 88.2%, and only 3.5% had gain of gene copy number. Thus, 97.2% (554/570) of acquiring ID-1 to 4 genes or loss of the E2A gene was observed in most ovarian cancer patients with ID gene acquisition or loss of E2A gene .

2 (a) to (d) show the results of analyzing the relationship between the number of copies of ID genes and mRNA expression in 570 ovarian adenocarcinomas obtained from the TCGA data.

As shown in FIGS. 2 (a) to 2 (d), when the expression of the ID gene was analyzed according to the number of gene copies, ID-1 mRNA expression was decreased in the presence of ID-1 gene loss, , But there was no significant change compared with other tumors. The ID-2 gene tended to show slightly increased mRNA expression in most cases, but the expression of ID-3 gene remained unchanged. However, mRNA expression of ID-4 gene was increased in most cases regardless of the number of copies.

3 (a) to (d) show the results of analysis of the relationship between the degree of methylation of the ID gene and mRNA expression in 570 ovarian adenocarcinomas obtained from the TCGA data.

As shown in FIGS. 3 (a) to 3 (d), in the analysis of the relationship between the degree of methylation of the ID gene and mRNA expression, ID-1 to 4 genes were hypo-methylated in most of them, 2 and ID-4 mRNA expression was increased, but the increase and decrease of mRNA expression of ID-1 and ID-3 was not regular.

The results of analysis of the relationship between the number of E2A gene copies and mRNA expression in 570 ovarian adenocarcinomas obtained from the TCGA data are shown in FIG. 4 (a), and the methylation and mRNA expression of the E2A gene The results of analyzing the relationship are shown in Fig. 4 (b).

As shown in FIG. 4, the expression of the E2A gene was analyzed according to the number of gene copies. As a result, the expression of mRNA was decreased in most cases. In particular, the more the E2A gene was lost, the more the mRNA expression was decreased. The expression was also decreased in ovarian cancer (Fig. 4 (a)). In addition, the E2A gene was hypermethylated in most cases and the expression of mRNA was also decreased (FIG. 4 (b)).

5 (a) shows the result of analysis of the ID gene of the ovarian cancer stage and the copy number of the E2A gene in the 570 ovarian adenocarcinoma patients obtained from the TCGA data. The results of the methylation analysis of each gene are shown in 5 (b).

As shown in FIG. 5, the change in the number of replication of the ID gene in ovarian cancer tissues is not related to the stage, and ID gene is mostly amplified. The E2A gene is mostly deleted. In particular, the increase of the ID-1 gene was apparent (Fig. 5 (a)). On the other hand, as a result of DNA methylation analysis, the promoter of the ID gene was under-methylated regardless of the stage in ovarian cancer tissues, but the promoter of the E2A gene was hypermethylated (Fig. 5 b)).

The results of comparing mRNA expression changes of ID gene and E2A gene in early ovarian cancer (stage 1) and advanced ovarian cancer (stage 3C, 4) in 570 ovarian adenocarcinomas obtained from the TCGA data are shown in FIG. 6 Respectively.

As shown in FIG. 6, the expression of the E2A gene was further increased in the early stage ovarian cancer (stage 1), but the expression of the ID gene was not different according to the stage of ovarian cancer.

Also, FIG. 7 shows OncoPrint analysis of gene changes of IDs 1 to 4 in 570 ovarian adenocarcinomas obtained from the TCGA data.

As shown in Fig. 7, oncoPrint analysis of the ID1-4 gene showed that the gene was changed in 28% (161/575) of ovarian cancer, and the number of genes was almost not decreased, And there is no case where it is decreased.

The results of Kaplan-Meier evaluation of gene changes and overall survival time of IDs 1 to 4 in 570 ovarian adenocarcinomas obtained from the TCGA data are shown in FIG.

As shown in FIG. 8, the survival rate of the ID1-4 gene group and the group without the ID1-4 gene was found to be worse than that of the ID-3 gene group.

[Example 2] Ovarian cancer cell death by E47 protein expression

To establish an ovarian cancer cell line capable of regulating the expression of the E47 protein, the E47 ^mer gene was introduced into the SKOV-3 / Luc cell line using a retrovirus. In the E47 ^mer gene, the CD25 gene is ligated together. Therefore, in the cells in which the E47 ^mer gene has been inserted, CD25 is expressed in the cell membrane. Only the cells successfully inserted with the E47 ^mer gene are analyzed by FACS analysis using an antibody against CD25, 3 / Luc / E47 ^mer cell line. However, the E47 protein produced by the gene is a protein associated with a modified estrogen receptor. In the absence of tamoxifen, the E47 protein does not migrate into the nucleus but stays only in the cytoplasm. When Tamoxifen is administered, the modified estrogen of the E47 protein Binds to the receptor and moves the E47 protein to the nucleus to functionally activate the E47 protein.

Therefore, in order to activate the E47 protein, the culture medium of SKOV-3 / Luc cell line and SKOV-3 / Luc / E47 ^mer cell line was treated with tamoxifen (4 uM), and after 24, 48 and 72 hours, The growth change was observed under a microscope (magnification: 200). The results are shown in Fig. 9, and the number of cells was measured. The results are shown graphically in Fig.

9 and 10, tamoxifen was treated with ovarian cancer cell lines (SKOV-3 / Luc, OVCAR-3) in which E47 ^mer was inserted in-vitro to activate E47 ^mer protein As a result, the growth of cancer cells is stopped, and in particular, in SKOV-3 cells, the number of cells gradually decreases and all the cells die after 72 hours.

[Example 3] Ovarian cancer cell death by E47 protein expression

3,000,000 / 300 uL of SKOV-3 / Luc cell line obtained in Example 2 and SKOV-3 / Luc / E47 ^mer obtained in Example 2 were implanted subcutaneously into NSG mice and after 3 days, Tamoxifen pellet (25 mg) The effects of ovarian cancer cell line SKOV-3 / Luc on tumorigenesis and growth were analyzed. The changes in size of the tumor were measured weekly using ultrasound. The results are shown in FIG. 11, and the result of photographing small-animal optical imaging (BLI) at day 77 is shown in FIG. In the BLI, a luciferin solution (15 mg / ml or 30 mg / kg, in PBS, dose of 150 mg / kg) was injected into the abdominal cavity using the Xenogen IVIS Imaging System. The luminescence was measured at intervals of 2 minutes between and using the maximum value.

As shown in FIGS. 11 and 12, in the SKOV-3 / Luc transplanted mouse model, the size of the tumor sharply increases with time. However, in the SKOV-3 / Luc / E47 ^mer transplanted mouse model, tamoxifen pellet In the mouse model of SKOV-3 / Luc transplantation, the size of the tumor rapidly increases with time, although it can be seen that no tumor was formed in the mice induced to express E47.

As described above, when the E47 protein of the present invention is used, it can be seen that proliferation of ovarian cancer cells is effectively inhibited in both in-vitro and in-vivo, and thus it is found that it is effective in the prevention or treatment of ovarian cancer.

[Comparative Example 1] Comparison of apoptotic effect of E47 protein expression in pancreatic cancer

To compare the effect of the E47 protein on pancreatic cancer, the E47 ^mer gene was introduced into pancreatic cancer cell line PANC-1 using a retrovirus. In the E47 ^mer gene, the CD25 gene is ligated together. Therefore, in the cell in which the E47 ^mer gene is inserted, CD25 is expressed in the cell membrane. By using FACS analysis using the antibody against CD25, only the cells in which the E47 ^mer gene has been successfully inserted are isolated, Respectively.

In order to activate the E47 protein, the number of cells was measured after 2, 4, 6 and 8 days after treatment with tamoxifen (4 uM) in the culture medium of the cell line and cell line. The results are shown in FIG.

As shown in FIG. 13, when tamoxifen was treated with the E47 ^mer -inserted pancreatic cancer cell line in-vitro, the number of pancreatic cancer cells was slightly decreased, but compared with the effect of the ovarian cancer shown in FIG. 9 As a result, it can be confirmed that the proliferation inhibitory effect is remarkably excellent in ovarian cancer.

[Comparative Example 2] Comparison of apoptotic effect of E47 protein expression in pancreatic cancer

3,000,000 / 300uL was subcutaneously transplanted into the NSG mice and the cell line obtained in the above Comparative Example 1, and after 3 days, Tamoxifen pellet (25mg) was implanted subcutaneously in another site to affect tumor growth and growth of pancreatic cancer cell line Respectively. The changes in tumor size were measured weekly using ultrasound and the results are shown in FIG.

As shown in FIG. 14, the expression of E47 was induced using tamoxifen pellet in the transplantation mouse model, and as a result, the tumor was eventually formed, unlike in Example 3 above.

As a result, it can be seen that the E47 protein of the present invention is remarkably excellent in growth inhibition effect particularly in ovarian cancer.

<110> Industry-Academic Cooperation Foundation, Yonsei University <120> Pharmaceutical composition for preventing or treating ovarian          cancer <130> DPB162700 <160> 1 <170> KoPatentin 3.0 <210> 1 <211> 651 <212> PRT <213> homo sapiens <400> 1 Met Asn Gln Pro Gln Arg Met Ala Pro Val Gly Thr Asp Lys Glu Leu   1 5 10 15 Ser Asp Leu Leu Asp Phe Ser Met Met Phe Pro Leu Pro Val Thr Asn              20 25 30 Gly Lys Gly Arg Pro Ala Ser Leu Ala Gly Ala Gln Phe Gly Gly Ser          35 40 45 Gly Leu Glu Asp Arg Pro Ser Ser Gly Ser Trp Gly Ser Gly Asp Gln      50 55 60 Ser Ser Ser Phe Asp Pro Ser Arg Thr Phe Ser Glu Gly Thr His  65 70 75 80 Phe Thr Glu Ser Ser Ser Leu Ser Ser Ser Thr Phe Leu Gly Pro                  85 90 95 Gly Leu Gly Gly Lys Ser Gly Glu Arg Gly Ala Tyr Ala Ser Phe Gly             100 105 110 Arg Asp Ala Gly Val Gly Gly Leu Thr Gln Ala Gly Phe Leu Ser Gly         115 120 125 Glu Leu Ala Leu Asn Ser Pro Gly Pro Leu Ser Pro Ser Gly Met Lys     130 135 140 Gly Thr Ser Gln Tyr Tyr Pro Ser Tyr Ser Gly Ser Ser Arg Arg Arg 145 150 155 160 Ala Ala Asp Gly Ser Leu Asp Thr Gln Pro Lys Lys Val Arg Lys Val                 165 170 175 Pro Pro Gly Leu Pro Ser Ser Val Tyr Pro Pro Ser Ser Gly Glu Asp             180 185 190 Tyr Gly Arg Asp Ala Thr Ala Tyr Pro Ser Ala Lys Thr Pro Ser Ser         195 200 205 Thr Tyr Pro Ala Pro Phe Tyr Val Ala Asp Gly Ser Leu His Ser Ser     210 215 220 Ala Glu Leu Trp Ser Pro Pro Gly Gln Ala Gly Phe Gly Pro Met Leu 225 230 235 240 Gly Gly Ser Ser Pro Leu Pro Leu Pro Pro Gly Ser Gly Pro Val                 245 250 255 Gly Ser Ser Gly Ser Ser Ser Thr Phe Gly Gly Leu His Gln His Glu             260 265 270 Arg Met Gly Tyr Gln Leu His Gly Ala Glu Val Asn Gly Gly Leu Pro         275 280 285 Ser Ala Ser Ser Phe Ser Ser Ala Pro Gly Ala Thr Tyr Gly Gly Val     290 295 300 Ser Ser His Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Leu Gly Ser 305 310 315 320 Arg Gly Thr Thr Ala Gly Ser Ser Gly Asp Ala Leu Gly Lys Ala Leu                 325 330 335 Ala Ser Ile Tyr Ser Pro Asp His Ser Ser Asn Asn Phe Ser Ser Ser             340 345 350 Pro Ser Thr Pro Val Gly Ser Pro Gln Gly Leu Ala Gly Thr Ser Gln         355 360 365 Trp Pro Arg Ala Gly Ala Pro Gly Ala Leu Ser Pro Ser Tyr Asp Gly     370 375 380 Gly Leu His Gly Leu Gln Ser Lys Ile Glu Asp His Leu Asp Glu Ala 385 390 395 400 Ile His Val Leu Arg Ser His Ala Val Gly Thr Ala Gly Asp Met His                 405 410 415 Thr Leu Leu Pro Gly His Gly Ala Leu Ala Ser Gly Phe Thr Gly Pro             420 425 430 Met Ser Leu Gly Gly Arg His Ala Gly Leu Val Gly Gly Ser His Pro         435 440 445 Glu Asp Gly Leu Ala Gly Ser Thr Ser Leu Met His Asn His Ala Ala     450 455 460 Leu Pro Ser Gln Pro Gly Thr Leu Pro Asp Leu Ser Arg Pro Pro Asp 465 470 475 480 Ser Tyr Ser Gly Leu Gly Arg Ala Gly Ala Thr Ala Ala Ala Ser Glu                 485 490 495 Ile Lys Arg Glu Glu Lys Glu Asp Glu Glu Asn Thr Ser Ala Ala Asp             500 505 510 His Ser Glu Glu Glu Lys Lys Glu Leu Lys Ala Pro Arg Ala Arg Thr         515 520 525 Ser Ser Thr Asp Glu Val Leu Ser Leu Glu Glu Lys Asp Leu Arg Asp     530 535 540 Arg Glu Arg Arg Met Ala Asn Asn Ala Arg Glu Arg Val Arg Val Arg 545 550 555 560 Asp Ile Asn Glu Ala Phe Arg Glu Leu Gly Arg Met Cys Gln Met His                 565 570 575 Leu Lys Ser Asp Lys Ala Gln Thr Lys Leu Leu Ile Leu Gln Gln Ala             580 585 590 Val Gln Val Ile Leu Gly Leu Glu Gln Gln Val Arg Glu Arg Asn Leu         595 600 605 Asn Pro Lys Ala Ala Cys Leu Lys Arg Arg Glu Glu Glu Lys Val Ser     610 615 620 Gly Val Val Gly Asp Pro Gln Met Val Leu Ser Ala Pro His Pro Gly 625 630 635 640 Leu Ser Glu Ala His Asn Pro Ala Gly His Met                 645 650

Claims (9)

A pharmaceutical composition for preventing or treating cancer, comprising E47 protein as an active ingredient. The method according to claim 1,
Wherein said E47 protein is represented by the amino acid sequence of SEQ ID NO: 1. The method according to claim 1,
Wherein the pharmaceutical composition further comprises tamoxifen. The method according to claim 1,
Wherein the cancer is at least one selected from the group consisting of cervical cancer, stomach cancer, brain cancer, rectal cancer, colon cancer, lung cancer, skin cancer, blood cancer and liver cancer. 5. The method of claim 4,
Wherein said cancer is ovarian cancer. A pharmaceutical composition for inhibiting invasion and metastasis of cancer, comprising E47 protein as an active ingredient. The method according to claim 6,
Wherein said E47 protein is represented by the amino acid sequence of SEQ ID NO: 1. The method according to claim 6,
Wherein the pharmaceutical composition further comprises tamoxifen. The method according to claim 6,
Wherein said cancer is ovarian cancer.

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