CN112063721A - Application of MOF in liver cancer treatment - Google Patents

Application of MOF in liver cancer treatment Download PDF

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Publication number
CN112063721A
CN112063721A CN202011042051.2A CN202011042051A CN112063721A CN 112063721 A CN112063721 A CN 112063721A CN 202011042051 A CN202011042051 A CN 202011042051A CN 112063721 A CN112063721 A CN 112063721A
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China
Prior art keywords
mof
liver cancer
cancer
liver
small molecule
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CN202011042051.2A
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Chinese (zh)
Inventor
赵越
王春玉
尉姗
王胜利
邹仁龙
孙洪邈
林琳
曾凯
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China Medical University
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China Medical University
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    • C—CHEMISTRY; METALLURGY
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    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/45—Transferases (2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57438—Specifically defined cancers of liver, pancreas or kidney
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
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    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/118—Prognosis of disease development
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/91—Transferases (2.)
    • G01N2333/91045—Acyltransferases (2.3)
    • G01N2333/91051—Acyltransferases other than aminoacyltransferases (general) (2.3.1)
    • G01N2333/91057—Acyltransferases other than aminoacyltransferases (general) (2.3.1) with definite EC number (2.3.1.-)

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to application of MOF in liver cancer treatment. A liver cancer biomarker, wherein the biomarker is MOF gene/protein, and the use of the MOF gene/protein in the preparation of a kit for detecting liver cancer. Application of MOF or MOF small molecule agonist in preparing medicine and pharmaceutical composition for preventing or treating liver cancer. Experiments prove that the MOF can inhibit growth and invasion and metastasis of liver cancer of liver cells, and the MOF inhibits polyubiquitination degradation of estrogen receptors through acetylation of the 266 th, 268 th and 299 th lysines of the estrogen receptors, so that stability of estrogen receptor proteins is maintained. The MOF can inhibit liver cell liver cancer and prepare an MOF small molecular agonist so as to achieve the function of treating clinical liver cell cancer. The MOF plays a role in inhibiting cancer progression in the process of cancer occurrence and development, the expression of the MOF is down-regulated in most tissues of patients with liver cancer, and the MOF can promote the expression of the MOF to effectively inhibit liver cancer. The invention provides a new idea and a new target spot for treating liver cancer.

Description

Application of MOF in liver cancer treatment
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of MOF in liver cancer treatment.
Background
Primary liver cancers include hepatocellular carcinoma (HCC) (75% -85% of cases) and intrahepatic cholangiocarcinoma (10% -15% of cases) and other rare types. There were approximately 841,000 new cases and 782,000 deaths each year. In most parts of the world, men have 2 to 3 times as much morbidity and mortality as women. The incidence of liver cancer in postmenopausal women increases, and estrogen treatment can suppress this phenomenon. The prognosis for female liver cancer is better than that for male. The above clinical results all suggest that the estrogen pathway may play a protective role in HCC.
Current major treatments for HCC include hepatectomy, liver transplantation, and adjuvant chemotherapy and radiation therapy, but their 5-year survival rate remains poor due to frequent recurrence and intrahepatic metastases. Currently, only sorafenib and Lenvatinib are approved as first-line drugs to treat unresectable advanced HCC, but only to a certain extent to benefit survival. Therefore, there is a need to identify new therapeutic targets to improve current HCC treatments.
Mof (males present on the first), also known as lysine acetyltransferase 8 (KAT 8), is a member of the MYST (moz-ybf 2/sas3-sas2-tip 60) family, with highly conserved Histone Acetyltransferase (HATs) domains in various species. In addition to histone acetylation modifications, MOFs can acetylate non-histones, such as P53, FASN, LSD1, NoRC, and IRF 3. In many primary cancer tissues, MOF expression is reduced, including liver cancer, however the biological function and mechanism of action of MOF in liver cancer progression is not clear.
Disclosure of Invention
In view of the problems of the prior art, the present invention aims to provide the application of MOF in liver cancer treatment. Experiments prove that the MOF can inhibit growth and invasion and metastasis of liver cancer of liver cells, and the MOF inhibits polyubiquitination degradation of estrogen receptors through acetylation of the 266 th, 268 th and 299 th lysines of the estrogen receptors, so that stability of estrogen receptor proteins is maintained. The MOF can inhibit liver cell liver cancer and prepare an MOF small molecular agonist so as to achieve the function of treating clinical liver cell cancer.
In order to achieve the above object, the present invention adopts the following technical solutions.
A biomarker for liver cancer, which is a MOF gene/protein.
Application of MOF gene/protein in preparation of a kit for detecting liver cancer.
A kit for liver cancer detection or prognosis of liver cancer, the kit using MOF genes/proteins as detection targets.
Application of MOF or MOF small molecule agonist in preparing medicine and pharmaceutical composition for preventing or treating liver cancer.
The MOF small molecule agonist is selected from the group consisting of: an interfering molecule targeting MOF or a transcript thereof and capable of promoting MOF expression or transcription, comprising: shRNA, small interfering RNA, dsRNA, microrna, antisense nucleic acid, or a construct capable of expressing or forming said shRNA, small interfering RNA, dsRNA, microrna, antisense nucleic acid.
The MOF small molecule agonist is in any pharmaceutically therapeutically acceptable dosage form.
The MOF small molecule agonist is in any pharmaceutically therapeutically acceptable dose.
The pharmaceutical composition comprises the MOF or MOF small molecule agonist and other drugs of the MOF or MOF small molecule agonist, and pharmaceutically acceptable carriers and/or auxiliary materials.
The shRNA sequence is shown as SEQ ID NO. 1-SEQ ID NO. 2.
The small molecule agonists of the invention may be used by formulating pharmaceutical compositions by any means known in the art. Such compositions comprise the active ingredient in admixture with one or more pharmaceutically acceptable carriers, diluents, fillers, binders and other excipients, depending on the mode of administration and the dosage form envisaged. Therapeutically inert inorganic or organic carriers known to those skilled in the art include, but are not limited to, lactose, corn starch or derivatives thereof, talc, vegetable oils, waxes, fats, polyols such as polyethylene glycol, water, sucrose, ethanol, glycerol, and the like, various preservatives, lubricants, dispersants, flavoring agents. Moisturizers, antioxidants, sweeteners, colorants, stabilizers, salts, buffers and the like may also be added as needed to aid in the stability of the formulation or to aid in the enhancement of the activity or its bioavailability or to produce an acceptable mouthfeel or odor upon oral administration, formulations that may be used in such compositions may be in the form of their original compounds as such, or optionally in the form of their pharmaceutically acceptable salts, and the small molecule agonists of the present invention may be administered alone, or in various combinations, as well as in combination with other therapeutic agents. The compositions so formulated may be administered in any suitable manner known to those skilled in the art, as desired. In using the pharmaceutical compositions, a safe and effective amount of an inhibitor of the present invention is administered to a human, wherein the safe and effective amount is typically at least about 100 micrograms per kilogram of body weight for oral administration. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The medicine of the present invention may be prepared into various preparation forms. Including, but not limited to, tablets, solutions, granules, patches, ointments, capsules, aerosols or suppositories for transdermal, mucosal, nasal, buccal, sublingual or oral use.
The route of administration of the drug of the present invention is not limited as long as it exerts the desired therapeutic effect or prophylactic effect, and includes, but is not limited to, intravenous, intraperitoneal, intraarterial, oral, intramuscular, subcutaneous. In some cases, the administration may be systemic. In some cases topical administration.
The dose of the drug of the present invention is not limited as long as the desired therapeutic effect or prophylactic effect is obtained, and can be appropriately determined depending on the symptoms, sex, age, and the like. The dose of the therapeutic agent or prophylactic agent of the present invention can be determined using, for example, the therapeutic effect or prophylactic effect on a disease as an index.
Compared with the prior art, the invention has the following beneficial effects.
The invention discovers for the first time that MOF can inhibit growth and invasion and transfer of liver cancer of liver cells, and MOF inhibits polyubiquitination degradation of estrogen receptors through acetylation of lysine 266 th, 268 th and 299 th sites of the estrogen receptors, so as to maintain stability of estrogen receptor proteins. The MOF plays a role in inhibiting cancer progression in the process of cancer occurrence and development, the expression of the MOF is down-regulated in most tissues of patients with liver cancer, and the MOF can promote the expression of the MOF to effectively inhibit liver cancer. The invention provides a new idea and a new target spot for treating liver cancer.
Drawings
FIG. 1 is the shRNA sequence of MOF.
FIG. 2 shows the result of cell survival experiments using MOF stably knockdown HCCLM3 and HUH7 cells, and the MOF knockdown results show that HCC cell survival capacity is enhanced.
FIG. 3 shows the results of experiments on the invasion and migration of HUH7 cells stably knocked down by using constructed MOF, and the invasion and migration of HCC cells are increased by knocking down MOF.
FIG. 4 shows the experimental results of tumor-bearing mice, in which the tumor growth is accelerated by knocking down MOF.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings and examples. The following examples are only preferred embodiments of the present invention and are not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art without departing from the spirit and the principle of the present invention, and any modifications, equivalents, improvements, etc. made within the spirit and principle of the present invention shall fall within the protection scope of the present invention.
Examples
1. Preparing the agonist.
MOF small molecule agonists are designed based on MOF transcripts or amino acid sequences.
2.MOF and agonist applications.
(1) The hepatocyte hepatoma cell lines HCCLM3 and HUH7 were infected with shRNA lentiviral vectors directed against MOF, the shRNA sequences are shown in FIG. 1.
(2) As shown in figure 2, the constructed MOF stably knockdown HCCLM3 and HUH7 cells are used for cell survival experiments, and the results show that the MOF knockdown cell strains grow obviously faster. The specific method comprises the following steps: clone formation experiment, 2X 10 3The individual cells were seeded in 6-well plates, 10% of a serum culture medium containing deactivant was added, the cells were induced to culture for more than one week with E2 or absolute ethanol, and after formation of a clear colony point, the cells were fixed with 4% paraformaldehyde and stained with Coomassie blue dye. Growth curve experiment, 2X 103The individual cells were plated in 96-well plates, stimulated with E2 or absolute ethanol, measured at 490 nm absorbance for the specified time and analyzed using MTS (Promega).
(3) As shown in FIG. 3, the constructed MOF stably knockdown HUH7 cells are used for carrying out invasion and migration experiments, and the results show that the invasion and migration of the MOF knocked-down HUH7 cell strain are obviously faster. The specific method comprises the following steps: migration experiment, 2X 10 4Cells were seeded in 100ul serum-free medium in the upper chamber, 600ul 10% serum-containing medium was added to the lower chamber and fixed after 24 hoursAnd observing the staining condition of the cells. Invasion experiments, matrigel was first spread in the upper chamber, the rest was the same as migration experiments. After 48 hours, cell staining was observed by fixation.
(4) As shown in figure 4, tumor-bearing mice experiments showed that silencing MOF promoted the growth of the hepatocellular hepatoma cell line HCCLM3 xenograft tumors in mice in vivo. The specific method comprises the following steps: subcutaneous injection of 1X 10 6And (4) cells. Tumor diameter was measured weekly with electronic calipers. Tumor volume (cubic millimeters) was calculated as volume = short diameter/2 × long diameter/2. After four weeks, tumor-bearing mice were killed according to the humane animal treatment policy. All procedures for animal experiments have been performed according to ethical regulations approved by the animal ethics committee of chinese university of medical science.
Sequence listing
<110> university of Chinese medical science
<120> application of MOF in liver cancer treatment
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<170> PatentIn version 3.3
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<211> 25
<212> DNA
<213> Artificial sequence
<400> 1
GACCAAGACA GUGAAGGAUG CUGUA 25
<210> 2
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<212> DNA
<213> Artificial sequence
<400> 2
UACAGCAUCC UUCACUGUCU UGGUC 25

Claims (9)

1. A biomarker for liver cancer, wherein the marker is a MOF gene/protein.
Use of MOF gene/protein in the preparation of a kit for detecting liver cancer.
3. A kit for liver cancer detection or prognosis, wherein the kit uses MOF gene/protein as a detection target.
4, application of the MOF or MOF small molecule agonist in preparing medicines and pharmaceutical compositions for preventing or treating liver cancer.
5. The use of claim 4, wherein the MOF small molecule agonist is selected from the group consisting of: an interfering molecule targeting MOF or a transcript thereof and capable of promoting MOF expression or transcription, comprising: shRNA, small interfering RNA, dsRNA, microrna, antisense nucleic acid, or a construct capable of expressing or forming said shRNA, small interfering RNA, dsRNA, microrna, antisense nucleic acid.
6. The use of claim 4, further characterized in that the MOF small molecule agonist is in any pharmacotherapeutically acceptable dosage form.
7. The use of claim 4, further characterized in that the MOF small molecule agonist is in a dose that is acceptable for any pharmacotherapeutic treatment.
8. The use of claim 4, wherein the pharmaceutical composition comprises a MOF or MOF small molecule agonist and other drugs with MOF or MOF small molecule agonist and a pharmaceutically acceptable carrier and/or adjuvant.
9. The use of claim 5, wherein the shRNA sequence is as shown in SEQ ID NO. 1-SEQ ID NO. 2.
CN202011042051.2A 2020-09-28 2020-09-28 Application of MOF in liver cancer treatment Pending CN112063721A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202011042051.2A CN112063721A (en) 2020-09-28 2020-09-28 Application of MOF in liver cancer treatment

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202011042051.2A CN112063721A (en) 2020-09-28 2020-09-28 Application of MOF in liver cancer treatment

Publications (1)

Publication Number Publication Date
CN112063721A true CN112063721A (en) 2020-12-11

Family

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Country Status (1)

Country Link
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Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
LIU J.H.等: "Coordination of FOXA2 and SIRT6 suppresses the hepatocellular carcinoma progression through ZEB2 inhibition", 《CANCER MANAGEMENT AND RESEARCH》 *
POTE N.等: "The histone acetyltransferase hMOF promotes vascular invasion in hepatocellular carcinoma", 《LIVER INTERNATIONAL》 *
POTE，N.等: "The histone acetyltransferase hMOF promotes vascular invasion in hepatocellular carcinoma", 《LIVER INTERNATIONAL》 *
ZHANG J.等: "The histone acetyltransferase hMOF suppresses hepatocellular carcinoma growth", 《BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS》 *
李楠等: "hMOF与肿瘤关系的研究进展", 《解剖科学进展》 *

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Application publication date: 20201211