CN109758577A - The purposes of DHRS2 gene and its inhibitor in preparation treatment liver-cancer medicine - Google Patents
The purposes of DHRS2 gene and its inhibitor in preparation treatment liver-cancer medicine Download PDFInfo
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- CN109758577A CN109758577A CN201910198561.XA CN201910198561A CN109758577A CN 109758577 A CN109758577 A CN 109758577A CN 201910198561 A CN201910198561 A CN 201910198561A CN 109758577 A CN109758577 A CN 109758577A
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Abstract
The present invention provides a kind of purposes of DHRS2 gene and its inhibitor in preparation treatment liver-cancer medicine, the especially purposes in treatment DHRS2 gene high expression type liver-cancer medicine.The expression that DHRS2 in detection liver cancer sample strain is found by research, can identify the highly expressed liver cancer strain of DHRS2, and can further predict such liver cancer can be treated with DHRS2 gene inhibitor.The application has significant meaning for the dependent diagnostic of liver cancer and treatment.
Description
Technical field
The present invention relates to a kind of purposes of DHRS2 gene and its inhibitor in preparation treatment liver-cancer medicine, especially control
Treat the purposes in DHRS2 gene high expression type liver-cancer medicine.
Background technique
Malignant tumour is to threaten one of the greatest danger factor of people's health, and tumor mortality number nearly 200 is often only in China
Ten thousand people, economic loss caused by malignant tumour are up to more than 1,400 hundred million yuans.In China, liver cancer is in malignant tumour, morbidity
Rate ranked third, and be only second to lung cancer and gastric cancer, but dead number of cases ranked second, and be only second to lung cancer.The treatment method of liver cancer can divide at present
Four bulks, first is surgical operation (including hepatectomy and transplantation of liver), and second is blood vessel intervention, and third is that local ablation is controlled
It treats (including radio frequency, microwave, freezing, frost free heat exchanger etc.), is finally chemicotherapy and molecular targeted therapy, biological therapy
Deng.But in China, 80% or more liver cancer is all that could find that patient has often lost operative chance in advanced stage.And at present very
The target spot of more clinical medicines also faces quick drug resistance.
Chemotherapy is one for the treatment of most important means of malignant tumour, however, tumour cell is normal to chemotherapeutics generation drug resistance
Often eventually lead to chemotherapy failure.Drug resistance refers to that pathogen and tumour cell etc. reduce chemotherapeutic agent sensibility.
When drug cannot kill or inhibit cause of disease, one word of drug resistance is equal to drug dose failure or drug resistance.Target spot drug resistance is swollen
The main bugbear of tumor treatment.Tumor cell drug resistance is divided into internality (already present when not in contact with drug) and acquired (contact
Generated after drug) two major classes.In general, drug resistance is generated to a kind of anti-tumor drug, it may be to structure and function phase
As drug generate cross resistance, but it is still sensitive to the drug of other different kind.Discovered in recent years contacts in culture solution
Certain chemotherapeutics and generate drug resistant cell strain, drug resistance is also generated to drugs unrelated in other structures, that mechanism of action is different,
This wide spectrum drug resistance phenomenon is known as multidrug resistance.
DHRS2 gene I/D: 10202, it mainly adjusts the enzyme of the gene of metabolism, and steroid hormone, prostate is adjusted
Element, biostearin etc..
It is had not been reported at present about the relationship of DHRS2 and liver cancer.
Summary of the invention
In view of the foregoing deficiencies of prior art, the purpose of the present invention is to provide a kind of DHRS2 gene inhibitors to exist
Purposes in preparation treatment DHRS2 gene high expression type liver-cancer medicine, for solving DHRS2 gene high expression type in the prior art
The ineffective problem of liver cancer treatment.
Based on research inventor discovery by the expression of DHRS2 in detection liver cancer sample strain, DHRS2 high can be identified
The liver cancer strain of expression, and can further predict such liver cancer strain and can be treated with DHRS2 gene inhibitor.It is above-mentioned to realize
Purpose and other related purposes, inventor provide following scheme:
One aspect of the present invention provides a kind of DHRS2 gene inhibitor and is preparing or screening the use in treatment liver-cancer medicine
On the way.
Further, the liver cancer refers to DHRS2 gene high expression type liver cancer.
Above-mentioned DHRS2 gene high expression is compared with other hypotypes of liver cancer tumor strain, more than expression quantity difference an order of magnitude
(10 times are a data level), (TPM value refers in every million cell for result TPM > 1000 that obtain of specific data reference sequencing data
Transcript number).
Above-mentioned therapeutic agent is at least one of with the following functions: inhibiting the increment of tumour cell, blood vessel hyperplasia, inhibits tumour
It is formed, vascularization.
Above-mentioned DHRS2 gene inhibitor can reduce the expression of DHRS2 gene.
DHRS2 gene inhibitor can be siRNA, shRNA, antibody, small molecule compound.
The drug necessarily includes DHRS2 gene inhibitor, and using DHRS2 gene inhibitor as the effective of aforementioned function
Ingredient.
In the drug, the effective component for playing aforementioned function can be only DHRS2 gene inhibitor, also may include that other can
Play the molecule of similar function.
Also that is, DHRS2 gene inhibitor is one of sole active ingredient or effective component of the drug.
The drug can be single composition substance, also can be multi-component compound.
The form of the drug can be the various substance shapes such as solid, liquid, gel, semi-fluid, aerosol without specifically limited
Formula.
The drug mainly for object be mammal, such as rodent, primate.
Another aspect of the present invention provides a kind of drug for treating liver cancer, includes effective therapeutic dose in the drug
DHRS2 gene inhibitor.
The drug necessarily includes DHRS2 gene inhibitor, and using DHRS2 gene inhibitor as the effective of aforementioned function
Ingredient.
In the drug, the effective component for playing aforementioned function can be only DHRS2 gene inhibitor, also may include that other can
Play the molecule of similar function.
Also that is, DHRS2 gene inhibitor is one of sole active ingredient or effective component of the drug.
The drug can be single composition substance, also can be multi-component compound.
The form of the drug can be the various substance shapes such as solid, liquid, gel, semi-fluid, aerosol without specifically limited
Formula.
The drug mainly for object be mammal, such as rodent, primate.
Further, the liver cancer refers to DHRS2 gene high expression type liver cancer.
Another aspect of the present invention provides a kind of method for treating liver cancer, to apply the suppression of DHRS2 gene to object
Preparation.
The object can be the liver cancer cells of mammal or mammal.The mammal is preferably Rodentia
Animal, artiodactylous animals, Perissodactyla animal, Lagomorph, primate etc..The primate is preferably monkey, ape
Or people.
The object can be the patient of suffering from hepatic cancer or the individual of Waiting treatment liver cancer.Or the object is liver cancer
The Hepatoma Cells In Vitro of the individual of patient or Waiting treatment liver cancer.
The DHRS2 gene inhibitor can be applied before, during and after receiving liver cancer treatment to object.
Another aspect of the invention provides a kind of liver cancer combination therapy pharmaceutical composition, the DHRS2 including therapeutically effective amount
Inhibit and other at least one cancer treatment drugs.
The combination therapy pharmaceutical composition can be any one in following form:
One) independent preparation is respectively prepared in DHRS2 inhibitor and other cancer treatment drugs, the dosage form of preparation can be identical
Or it is different, administration route also may be the same or different.
When other cancer treatment drugs are antibody, parenteral type is generally used.When other cancer treatment drugs are
When chemicals, form of medication can be relatively abundanter, and can be gastrointestinal administration can also be parenteral administration.It is general to recommend
For the known administration route administration of each chemicals.
Two) DHRS2 inhibitor and other cancer treatment drugs are configured to compound preparation, by DHRS2 inhibitor and its
When his cancer treatment drug is simultaneously applied simultaneously using the administration of identical administration route, the shape that the two is configured to compound preparation can be used
Formula.
Another aspect of the invention provides a kind of method for treating liver cancer, to apply a effective amount of DHRS2 suppression to object
Preparation and a effective amount of other cancer treatment drugs are applied to object and/or implement other liver cancer treatment means to object.
A effective amount of DHRS2 inhibitor can concurrently or sequentially be given and other at least one a effective amount of liver cancer are controlled
Treat drug.
Be based on DHRS2 present invention firstly discovers that liver cancer treatment target spot, other liver cancer other than with DHRS2 inhibitor
In therapeutic agent drug combination, the effect of curative effect addition can be at least played, the therapeutic effect for liver cancer is further enhanced.
Other cancer treatment drugs include but is not limited to: antibody drug, chemicals or target medicinal etc..
The DHRS2 inhibitor can be gastrointestinal administration or parenteral.Other described cancer treatment drugs can
To be gastrointestinal administration or parenteral.For antibody drug, parenteral is generally used.
Another aspect of the present invention, providing DHRS2 inhibitor in preparation has any one of following or multinomial effect medicine
Purposes in object: inhibit the multiplication rate of liver cancer cells, change liver cancer cells period profile, promote hepatoma cell apoptosis, inhibit
Liver cancer tissue growth.
Another aspect of the present invention provides DHRS2 and is preparing or screening the purposes in diagnosing cancer of liver reagent.
Further, the liver cancer is DHRS2 gene high expression type liver cancer.
Further, the DHRS2 is biomarker.For example, serum biomarkers.
Above content includes two aspects, first, DHRS2 is used to prepare diagnosing cancer of liver reagent, is referred to using DHRS2 as liver cancer
Diagnosis index is applied to the preparation of diagnosing cancer of liver reagent, can be using DHRS2 as standard items or positive control, in serum
The detection of DHRS2；Second, DHRS2 refers to for screening liver cancer using DHRS2 as liver cancer identification target sieving specific recognition
The reagent of DHRS2, thus as diagnosing cancer of liver reagent, to detect DHRS2 gene high expression type liver cancer.
Further, the liver cancer refers to DHRS2 gene high expression type liver cancer.
Another aspect of the present invention provides purposes of the specific recognition agent of DHRS2 in diagnosing liver cancer.DHRS2
It can be used as a kind of biomarker.
Further, the liver cancer refers to DHRS2 gene high expression type liver cancer.
Another aspect of the present invention provides DHRS2 specific recognition agent in the diagnostic reagent for preparing diagnosing liver cancer
Purposes.
Further, the liver cancer refers to DHRS2 gene high expression type liver cancer.
DHRS2 specific recognition agent is the antibody or ligand for referring to specific binding DHRS2.Further, described
Antibody is monoclonal antibody or polyclonal antibody.
Another aspect of the present invention provides a kind of diagnostic kit of liver cancer, contains specificity in the kit
Identify the reagent of DHRS2.
Further, the liver cancer refers to DHRS2 gene high expression type liver cancer.
Another aspect of the present invention provides a kind of method for screening cancer treatment drug, which comprises
(3) system of expression DHRS2 is handled with candidate substances；With
(2) expression of DHRS2 in the system is detected.
As described above, the purposes of DHRS2 gene inhibitor of the invention in preparation treatment liver-cancer medicine, has with following
Beneficial effect:
By the study found that DHRS2 high expression type liver cancer sample strain can effectively be pressed down using the expression of inhibitor inhibition DHRS2
Liver cancer growth processed, effective percentage reach 50% or more.
Detailed description of the invention
Fig. 1 is shown as in embodiment 1 imitating liver cancer treatment after inhibiting DHRS2 based on the highly expressed hepatoma cell strain of DHRS2
The schematic diagram of fruit.
Fig. 2 shows the highly expressed schematic illustration of tissue of DHRS2 in human protein database.
Specific embodiment
Illustrate embodiments of the present invention below by way of specific specific example, those skilled in the art can be by this specification
Other advantages and efficacy of the present invention can be easily understood for disclosed content.The present invention can also pass through in addition different specific realities
The mode of applying is embodied or practiced, the various details in this specification can also based on different viewpoints and application, without departing from
Various modifications or alterations are carried out under spirit of the invention.It should be clear that the process equipment or device that are not indicated specifically in the following example
It is all made of conventional equipment or device in the art.
Before further describing the specific embodiments of the present invention, it should be appreciated that protection scope of the present invention is not limited to down
State specific specific embodiment；It is also understood that term used in the embodiment of the present invention is specific specific in order to describe
Embodiment, rather than limiting the scope of protection of the present invention；In description of the invention and claims, unless in text
In addition explicitly point out, singular "one", " one " and " this " include plural form.
When embodiment provides numberical range, it should be appreciated that except non-present invention is otherwise noted, two ends of each numberical range
Any one numerical value can be selected between point and two endpoints.Unless otherwise defined, the present invention used in all technologies and
Scientific term is identical as the normally understood meaning of those skilled in the art of the present technique.Except specific method, equipment used in embodiment,
Outside material, grasp and record of the invention according to those skilled in the art to the prior art can also be used and this
Any method, equipment and the material of the similar or equivalent prior art of method described in inventive embodiments, equipment, material come real
The existing present invention.
DHRS2 is the enzyme for mainly adjusting the gene being metabolized, adjustable steroid hormone, prostaglandin, biostearin etc.,
Its sequence can refer to NCBI.ID:10202.
Research is found: DHRS2 only has expression in salivary gland and urethral tissue in normal human tissue, by cutting to liver cancer
Except pattern detection, when discovery DHRS2 high expression can preliminary judgement be liver cancer tumor strain to using BRD4 inhibitor insensitive.It is real
It issues after examination and approval now, carries out inhibiting to make DHRS2 gene drug resistant to BRD4 inhibitor high for DHRS2 gene high expression type liver cancer
The increment of expression type liver cancer cells is significantly inhibited, therefore is had to DHRS2 gene high expression type liver cancer treatment significant
Therapeutic potential.
DHRS2 gene inhibitor
DHRS2 gene inhibitor has the function of inhibiting the substance of DHRS2 gene expression.Can have for DHRS2 gene
Inhibiting effect includes but is not limited to: reducing the transcription or expression of DHRS2 gene.
Inhibitor using DHRS2 gene is the oncotherapy of one of main active ingredient or main active ingredient preparation
Drug.In general, will also include one or more according to the needs of different dosage forms in addition to effective ingredient in drug and pharmaceutically may be used
The carrier or auxiliary material of receiving.
" pharmaceutically acceptable " refer to when biomolecule ontology and composition is appropriate give animal or people when, they will not
Generate unfavorable, allergy or other adverse reactions.
" pharmaceutically acceptable auxiliary material " refers to should be compatible with DHRS2 inhibitor, can be blended without logical
The effect of pharmaceutical composition is greatly lowered in normal situation.It can be used as some substances of pharmaceutically acceptable carrier or auxiliary material
Specific example is carbohydrate, such as lactose, dextrose and saccharose；Starch, such as cornstarch and potato starch；Cellulose and its derivative
Object, such as sodium carboxymethylcellulose pyce, ethyl cellulose and methylcellulose；Tragacanth powder；Malt；Gelatin；Talcum；Solid lubrication
Agent, such as stearic acid and magnesium stearate；Calcium sulfate；Vegetable oil, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and can
It can oil；Polyalcohol, such as the third two liquor-saturated, glycerol, D-sorbite, mannitol and polyethylene glycol；Alginic acid；Emulsifier, such as Tween；
Wetting agent, such as NaLS；Colorant；Flavoring agent；Tablet agent, stabilizer；Antioxidant；Preservative；Apirogen water etc.,
Seep salting liquid；With phosphate buffer etc..These substances are used to help the stability of formula as needed or help to improve work
Property or its biological effectiveness generate acceptable mouthfeel or smell in the case where oral.
Combination therapy pharmaceutical composition and method of administration:
The combination therapy pharmaceutical composition can be any one in following form:
One) independent preparation is respectively prepared in DHRS2 gene inhibitor and other cancer treatment drugs, the dosage form of preparation can
Identical or different, administration route also may be the same or different.In use, can several medicines use simultaneously, can also several medicines successively use.
When consecutive administration, formerly still it should apply other drugs to body in body effective period with drug.
Two) DHRS2 gene inhibitor and other cancer treatment drugs are configured to compound preparation, inhibited in DHRS2 gene
Agent and other cancer treatment drugs can be used the two being configured to compound system using the administration of identical administration route and when applying simultaneously
The form of agent.
A effective amount of DHRS2 gene inhibitor and other at least one a effective amount of livers can concurrently or sequentially be given
Cancer therapeutic agent.
In use, a effective amount of DHRS2 gene inhibitor and other a effective amount of cancer treatment drugs can be used simultaneously,
A effective amount of DHRS2 gene inhibitor and other a effective amount of cancer treatment drugs can also successively be used.When consecutive administration, answer
Still apply other drugs to organism in organism effective period with drug when formerly.
Hepatoma cell proliferation is suppressed after DHRS2 inhibits in one DHRS2 high expression type tumor strain of embodiment
Choose the liver cancer tumor strain of different subtype: HepG2, Hep3B (being purchased from Chinese Academy of Sciences's cell classical collection center) are extracted
RNA, the method being sequenced using two generations carry out RNA seq sequencing, the expression quantity of available difference tumor strain TPM value.Based on sequencing
The expression TPM of DHRS2 in two kinds of obtained hepatic carcinoma gene expression datas.Referring specifically to table 1.
Table 1
| Gene Name | TPM0hrep1_HepG2 | TPM0hrep2_HepG2 | TPM0hrep1_Hep3B | TPM0hrep2_Hep3B |
| DHRS2 | 3093.3 | 3003.64 | 0.75 | 0.51 |
It can be seen that the DHRS2 value of different liver cancer hypotypes has apparent difference.
TPM value is selected to be greater than 1000, as the tumor strain that can inhibit liver cancer growth after inhibition DHRS2.It is right by 96 orifice plates
After being knocked out DHRS2 using RNA I method, the HepG2 cell before knocking out and after knocking out carries out bed board, every hole 100ul training
Support base, 2000 cells detect first day by cell proliferation experiment kit CTG (be purchased from promega), and second day, third
It, the 4th day, the fluorescence at the 5th day five time points counted, and with first day reading for 100%, calculated different number of days cell
Growth pattern.
It is counted by result, discovery enhanced with the time, and the effect of growth is inhibited to be more and more obvious, and the 5th day when can press down
The cell growth of system 50%.As a result as shown in Figure 1, the results showed that liver cancer cells after DHRS2 inhibits in DHRS2 high expression type tumor strain
Proliferation is significantly inhibited.
The specificity that two DHRS2 gene inhibitor of embodiment treats DHRS2 high expression type tumor strain
Fig. 2 is shown as the highly expressed schematic illustration of tissue of DHRS2 in human protein database.(the flat human protein of data source
Database: Human protein Altas)
From Figure 2 it can be seen that having expression in only salivary gland and urethral tissue in DHRS2 normal tissue.When liver cancer cuts off sample
Can be used when detection DHRS2 high expression inhibits DHRS2 to be treated, and will not injure other normal tissues, therefore this Shen
It can please specifically be directed to the highly expressed hepatocarcinoma patient of DHRS2.
Above embodiment is can not to be interpreted as in order to illustrate embodiment disclosed by the invention to limit of the invention
System.In addition, in various modifications and invention listed herein method, composition variation, do not departing from the scope of the present invention
Be obvious for those skilled in the art under the premise of spirit.Although having combined of the invention a variety of specific
Preferred embodiment has carried out specific description to the present invention, it is to be understood that, the present invention should not be limited only to these specific embodiments.
In fact, various obviously modify as described above for those skilled in the art to obtain invention all should include
Within the scope of the invention.
Claims (10)
1.DHRS2 gene inhibitor is preparing or is screening the purposes in treatment liver-cancer medicine.
2. purposes according to claim 1, which is characterized in that the liver cancer is DHRS2 gene high expression type liver cancer.
3. a kind of cancer treatment drug, which is characterized in that include the DHRS2 gene inhibitor of effective therapeutic dose in the drug.
4. a kind of liver cancer combination therapy pharmaceutical composition, which is characterized in that described pharmaceutical composition includes to control the DHRS2 of therapeutically effective amount
Inhibit and other at least one cancer treatment drugs.
5.DHRS2 is preparing or is screening the purposes in diagnosing cancer of liver reagent.
Purposes of the 6.DHRS2 specific recognition agent in the diagnostic reagent for preparing diagnosing liver cancer.
7. a kind of diagnostic kit of liver cancer, the reagent containing specific recognition DHRS2 in the kit.
8. the diagnostic kit of liver cancer according to claim 7, which is characterized in that the liver cancer is the high table of DHRS2 gene
Up to type liver cancer.
Purposes of the 9.DHRS2 as biomarker.
10. a kind of method for screening cancer treatment drug, which comprises
(1) system of expression DHRS2 is handled with candidate substances；With
(2) expression of DHRS2 in the system is detected.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104755627A (en) * | 2012-09-21 | 2015-07-01 | 英特盖根公司 | A new method for classification of liver samples and diagnosis of focal nodule dysplasia, hepatocellular adenoma, and hepatocellular carcinoma |
-
2019
- 2019-03-15 CN CN201910198561.XA patent/CN109758577A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104755627A (en) * | 2012-09-21 | 2015-07-01 | 英特盖根公司 | A new method for classification of liver samples and diagnosis of focal nodule dysplasia, hepatocellular adenoma, and hepatocellular carcinoma |
Non-Patent Citations (2)
| Title |
|---|
| CHAD DEISENROTH ET AL.: ""Mitochondrial HEP27 Is a c-Myb Target Gene That Inhibits Mdm2 and Stabilizes p53"", 《MOLECULAR AND CELLULAR BIOLOGY》 * |
| 褚晓磊等: ""肝细胞性肝癌中Hep27和MDM2蛋白的表达及意义"", 《临床与实验病理学杂志》 * |
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