CN116814625A - Mimic-QHSC-miRNA for preventing and/or treating hepatocellular carcinoma and application thereof - Google Patents

Mimic-QHSC-miRNA for preventing and/or treating hepatocellular carcinoma and application thereof Download PDF

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CN116814625A
CN116814625A CN202310792338.4A CN202310792338A CN116814625A CN 116814625 A CN116814625 A CN 116814625A CN 202310792338 A CN202310792338 A CN 202310792338A CN 116814625 A CN116814625 A CN 116814625A
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China
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mimic
mirna
qhsc
hepatocellular carcinoma
medicament
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Inventor
季菊玲
孙玉风
吕佳颖
张峻瑜
蒯兴旺
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Nantong University
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Nantong University
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering N.A.
    • C12N2310/141—MicroRNAs, miRNAs
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2320/00—Applications; Uses
    • C12N2320/30—Special therapeutic applications
    • C12N2320/32—Special delivery means, e.g. tissue-specific

Abstract

The invention discloses a mimic-QHSC-miRNA for preventing and/or treating hepatocellular carcinoma and application thereof, wherein the mimic-QHSC-miRNA is a mimic of miR-99a-5p, and the nucleotide sequence of the mimic-QHSC-miRNA is shown as SEQ ID NO. 1. The mimic-QHSC-miRNA of the invention obviously improves the occurrence and development of a transplanted tumor model in experiments through the direct action on liver cancer cells and the indirect action on tumor immune microenvironment, and can be used for clinically preventing/treating liver cell liver cancer. The medicine for inhibiting the hepatocellular carcinoma has high safety, strong pharmacological action and definite curative effect. The invention provides a new medicine source for preventing, diagnosing, detecting, protecting, treating and researching hepatocellular carcinoma, is easy to popularize and apply clinically, and can generate huge clinical application prospect and social benefit in a short time.

Description

Mimic-QHSC-miRNA for preventing and/or treating hepatocellular carcinoma and application thereof
Technical Field
The invention belongs to the field of biotechnology and medicine, and particularly relates to a mimic-QHSC-miRNA for preventing and/or treating hepatocellular carcinoma and application thereof.
Background
Hepatocellular carcinoma (hepatocellular carcinoma, HCC) is a major histological subtype of liver cancer, accounting for 75% -85% of primary liver cancer, and has high malignancy and poor prognosis, which seriously threatens the physical and mental health of human beings. The high death rate of liver cancer is largely due to the strong concealment, and the early diagnosis of liver cancer has a plurality of defects at present.
Liver fibrosis is caused by the conversion of activated inactive liver fibroblasts or hepatic stellate cells (hepatic stellate cell, HSCs) to collagenous cells following liver injury. In HCC, cancer-associated fibroblasts (CAF-associated fibroblast) are broadly defined as HSCs found in tumor masses. These CAFs are thought to be causative of carcinogenesis and homeostasis. These data indicate that activated HSCs play a critical role in the development of HCC. However, how activated hepatic stellate cells act on liver tumors is not known at present.
The initiation and duration of HSC activation is directly regulated by liver macrophages, a key driver of fibrogenesis, intimately associated with collagen-producing myofibroblasts. One key step at the onset of liver fibrosis is the strong inflammatory response. Chronic liver disease and related inflammation can lead to deposition of extracellular matrix (Extracellular matrix, ECM) to form liver fibrosis, which if left uncontrolled, will continue to accumulate as fibrous scars, ultimately leading to HCC. Tumor growth, metastasis and regression are affected by the microenvironment in which they are located. Tumor-associated macrophages (TAMs) are a major component of the tumor microenvironment, and their plasticity can differentiate into M1 and M2 phenotypes, playing an important role in the progression of HCC. It is currently widely believed that M2 macrophages promote tumor development by inducing proliferation and metastasis of tumor cells, while M1 macrophages have anti-tumor effects. Macrophages differentiate into different phenotypes under the stimulation of various factors, and show different characteristics and actions, thereby playing different regulatory roles on physiological and pathological activities of the organism. The pathogenesis of the liver disease is clarified, and the development of the targeted therapeutic drug has important significance for clinical treatment of the liver disease. In recent years, a large body of literature has shown that macrophage polarization may play an important role in the development and reversal of a variety of liver diseases, such as fatty liver, hepatitis, fibrosis, and HCC. With further investigation of macrophage polarization in liver disease, targeting macrophage polarization blocking and even reversing liver pathological changes has been considered as a potential strategy for treating liver disease.
Recent studies have shown that some miRNAs are associated with various liver diseases, including liver fibrosis, and recent evidence suggests that miRNAs play a critical role in the development and progression of HCC. According to current studies, miRNAs play an important role in macrophage polarization, and can regulate cellular differentiation and function of immune cells. In recent years, exosomes have been widely studied and used and proved to be important vectors for miRNA signaling. It functions not only in the starting cell, but also can be packaged into vesicles and released into the extracellular environment where it is transferred to other cells in an active form and functions.
The first treatment scheme of liver cancer is radical excision, but even if surgical excision is carried out, recurrence and metastasis still occur within 5 years for 60% -70% of patients, and recurrence after liver cancer excision is a major hidden danger of liver cancer treatment. In addition, the liver cancer treatment method also comprises chemical drug treatment, radiation treatment, biological treatment, traditional Chinese medicine treatment and the like. Although there are currently FDA approved drugs for clinical treatment of HCC, their therapeutic effect is quite limited. Therefore, the development of effective therapeutic agents is still a focus of attention by exploring the pathological mechanisms of hepatocellular carcinoma. Liver cancer prognosis is helpful for predicting survival of liver cancer patients, but traditional prognosis methods have limitations. Therefore, the biomarker related to liver cancer prognosis is searched, which is not only beneficial to the improvement of prognosis, but also beneficial to the targeted treatment of liver cancer. Along with the action of people on exosomes in tumor microenvironment, the exosomes are expected to bring new breakthroughs in tumor treatment and prognosis evaluation, and become important biological indexes. The research and design of the nano vesicle containing the high-level miRNA are expected to provide a new idea for the treatment of clinical liver cell liver cancer.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a mimic-QHSC-miRNA for preventing and/or treating hepatocellular carcinoma and application thereof, and the progress of HCC can be inhibited by regulating and controlling the expression of a target gene.
The invention is realized by the following technical scheme:
a mimic-QHSC-miRNA for preventing and/or treating hepatocellular carcinoma is a mimic of miR-99a-5p, and the nucleotide sequence of the mimic is shown in SEQ ID NO. 1.
The application of the mimic-QHSC-miRNA in preparing medicaments for preventing and/or treating hepatocellular carcinoma.
Preferably, the drug is a drug which directly acts on liver cancer cells to down regulate proliferation of cancer cells.
Preferably, the medicament is a medicament for improving the immune microenvironment of a hepatocellular carcinoma tumor.
Preferably, the drug is one that significantly induces macrophage polarization.
An anti-tumor product, wherein the active ingredient of the product is the mimic-QHSC-miRNA; the product is a medicine, an additive or an active ingredient agent; the uses of the product include at least one of the following uses:
(1) Inhibit proliferation of liver cancer cells;
(2) Inducing macrophage polarization to improve tumor immunity microenvironment;
(3) Inhibit the occurrence/development of liver cancer.
A pharmaceutical composition for preventing and/or treating hepatocellular carcinoma comprises the mimic-QHSC-miRNA and pharmaceutically added auxiliary materials.
Preferably, the auxiliary materials comprise one or more of diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers and lubricants.
Preferably, the pharmaceutical composition is in an oral or non-oral dosage form.
Preferably, the pharmaceutical composition is a tablet, capsule, powder, pill, granule, solution, suspension, syrup, injection, suppository, inhalant or spray.
The beneficial effects of the invention are as follows:
the mimic-QHSC-miRNA of the invention obviously improves the occurrence and development of a transplanted tumor model in experiments through the direct action on liver cancer cells and the indirect action on tumor immune microenvironment, and can be used for clinically preventing/treating liver cell liver cancer. The medicine for inhibiting the hepatocellular carcinoma has high safety, strong pharmacological action and definite curative effect. The invention provides a new medicine source for preventing, diagnosing, detecting, protecting, treating and researching hepatocellular carcinoma, is easy to popularize and apply clinically, and can generate huge clinical application prospect and social benefit in a short time.
Drawings
FIG. 1 is a graph of miR-99a-5p modulates THP1 macrophage phenotype, inhibiting growth of a subcutaneous tumor in example 2: a is an in-vitro tumor visual image (left), an in-vitro tumor weight (middle) and a nude mouse tumor growth curve (right) in a nude mouse transplanted tumor model; b is the immunohistochemistry of paraffin sections of in vitro tumor tissue (left) and Ki67 positive cell count (right); c is the expression level of MRC1 and INOS detected by Western Blot of tumor tissues;
FIG. 2 shows that in vitro miR-99a-5p regulates THP1 macrophages to inhibit liver cancer cell proliferation in example 3: a is a Huh7/HepG2 clone formation experiment of each group; b is a statistical plot of the number of Huh7/HepG2 clones formed for each group.
Detailed Description
The invention will be described in further detail with reference to the drawings and the specific embodiments.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
The THP1 cells in the following examples are derived from human leukemia mononuclear cells, and the HepG2 cells and Huh7 cells are derived from human liver cancer tissue, and are all purchased from stem cell bank of China academy of sciences.
The animals used in the examples below were 5 week old Balb/c nude mice, supplied by the university of Nantong laboratory animal center, purchased from Shanghai medical laboratory animal center.
Example 1
A mimic-QHSC-miRNA for preventing and/or treating hepatocellular carcinoma is a mimic of miR-99a-5p, and has a nucleotide sequence shown in SEQ ID NO.1, and specifically comprises the following components: AACCC GUAGA UCCGA UCUUG UG. Specific information for the mimic-QHSC-miRNA is shown in Table 1 below:
TABLE 1MImic-QHSC-miRNA information Table
Example 2miR-99a-5p modulates THP1 macrophage phenotype to inhibit growth of subcutaneous tumor
1. Establishing a nude mouse transplantation tumor model:
(1) miR-99a-5p mimetic (mimic-QHSC-miRNA) transfects THP1 cells which are already adhered by PMA induction in vitro, and the specific grouping is as follows:
CTRL group: blank (Blank) control, i.e. untreated HepG2 cells;
THP1 group: THP1 was mixed with HepG2 cells;
THP 1-mic-NC group: mixing the THP1 pretreated by the mimic-NC with the HepG2 cell;
THP 1-mic-99 a-5p group: miR-99a-5p mimetic-pretreated THP1 was mixed with HepG2 cells.
(2) After 24h of transfection, the cells were washed three times with 1 XPBS, trypsinized, centrifuged at 1000rpm for 5min at 4℃and the pellet resuspended in 1 XPBS and adjusted to 4X 10 after counting 5 /mL。
(3) HepG2 cells grown to logarithmic phase were washed three times with 1 XPBS, trypsinized, centrifuged at 1000rpm for 5min at 4℃and the cell pellet resuspended in 1 XPBS and adjusted to 2X 10 after counting 6 /mL。
(4) The treated THP1 cell suspension was mixed with the HepG2 cell suspension in equal volume, the ratio of cell numbers was 1:5, and placed on ice.
(5) Blowing and uniformly mixing the cell suspension in the step (3), and then inoculating the cell suspension to the subcutaneous position of the scapula on the right side of the nude mice by using an insulin syringe, wherein each nude mouse is injected with 100 mu L of THP1The cell number was 2X 10 5 HepG2 cell number was 1X 10 6 。
(6) Subcutaneous tumor growth was observed daily, and the subcutaneous tumor size and nude mouse body weight were measured every two days and recorded.
(7) After 4 weeks, the weight and volume of the isolated tumor were weighed, and a portion of the tumor tissue was sectioned into paraffin tissue and a portion of the protein was extracted.
2. Tumor growth curves were made according to each measurement of subcutaneous tumor size.
3. Immunohistochemical analysis of Ki67 expression.
4. Western Blot detects MRC1 and INOS expression levels in tumor tissues.
5. Statistical methods:
statistical analysis was performed using GraphPad Prism 6 software. For quantitative data, groups were reported as mean±sem, and differences between groups were compared for significance using unpaired two-tailed t-test or One-way ANOVA test, P < 0.05 indicating that differences were statistically significant. Unless otherwise indicated, all experiments were repeated three more times. The picture processing software Photoshop and Adobe Illustrator make puzzles, and Image J analyzes gray values of a Western Blot result graph.
6. Experimental results:
as shown in fig. 1, THP1 over-expression miR-99a-5p inhibited tumor progression in vivo: as shown in fig. 1 a, the hepg2+thp1-mic-99 a-5p group tumors were significantly reduced, and the weight of the isolated tumors was significantly reduced; as shown in fig. 1B, immunohistochemistry showed a significant decrease in Ki67 positive cell number; as shown in FIG. 1C, the Western Blot results showed a decrease in MRC1 expression levels and an increase in INOS expression levels.
Experimental results in the embodiment show that miR-99a-5p mimics can inhibit liver cancer cell proliferation and tumor growth by promoting macrophage differentiation to M1 pro-inflammatory and cancer-inhibiting phenotype.
EXAMPLE 3THP1 overexpression of miR-99a-5p inhibits liver cancer cell proliferation
1. Co-culturing the THP1 with a human liver cancer cell line Huh7/HepG2 after the miR-99a-5p is over-expressed:
(1) miR-99a-5p mimics in vitro transfection of PMA-induced adherent THP1 cells.
(2) THP1 was transfected for 24h, washed three times with 1 XPBS, trypsinized, centrifuged at 1000rpm for 5min at 4℃and the cell pellet resuspended in 1 XPBS and counted.
(3) HepG2 cells and Huh7 cells grown to log phase were washed three times with 1 XPBS, respectively, trypsinized, centrifuged at 1000rpm for 5min at 4℃and 1 XPBS to resuspend cell pellet, counted and seeded in 12-well plates, hepG2 was seeded 300 per well, huh7 was seeded 500 per well and divided into 4 groups of 3 multiplex wells.
(4) Adding the processed THP1 suspension into culture plate inoculated with HepG2 and Huh7 (i.e. 60 THP1 cells are added to each hole of the HepG2 cell culture plate and 100 THP1 cells are added to each hole of the Huh7 cell culture plate) according to the ratio of 1:5, and placing at 37 ℃ and 5% CO 2 Culturing in an incubator. The specific grouping is as follows:
CTRL group: blank (Blank) control, i.e., no treated Huh7 cells or HepG2 cells;
THP1 group: THP1 was mixed with Huh7 cells or HepG2 cells;
THP 1-mic-NC group: mixing the THP1 pretreated by the mimic-NC with Huh7 cells or HepG2 cells;
THP 1-mic-99 a-5p group: miR-99a-5p mimetic-pretreated THP1 was mixed with Huh7 cells or HepG2 cells.
(5) Observing the clone formation of Huh7 and HepG2 every day, culturing for about 7-10 days, washing with 1 XPBS 3 times, fixing cells with 2% paraformaldehyde at room temperature for 20min, removing paraformaldehyde, adding 500 μl of 0.1% crystal violet solution into each well, incubating at room temperature for 10min, recovering crystal violet solution, and adding ddH 2 O is washed 3 times, ddH is discarded after the last washing 2 And O, photographing and counting after airing, and counting the clone number of each hole.
2. Statistical methods:
statistical analysis was performed using GraphPad Prism 6 software. For quantitative data, groups were reported as mean±sem, and differences between groups were compared for significance using unpaired two-tailed t-test or One-way ANOVA test, P < 0.05 indicating that differences were statistically significant. Unless otherwise indicated, all experiments were repeated three more times. Picture processing software Photoshop, adobe Illustrator makes puzzles.
3. Experimental results:
as shown in FIG. 2, THP1 over-expression of miR-99a-5p significantly inhibited Huh7 and HepG2 clone formation.
Experimental results in this example show that the macrophage induced by miR-99a-5p mimic has the effect of inhibiting liver cancer cell proliferation.
The above embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by a person skilled in the art without any inventive effort, are intended to be within the scope of the present invention based on the embodiments of the present invention.

Claims (10)

1. The mimic-QHSC-miRNA for preventing and/or treating hepatocellular carcinoma is characterized in that the mimic-QHSC-miRNA is a mimic of miR-99a-5p, and the nucleotide sequence of the mimic-QHSC-miRNA is shown as SEQ ID NO. 1.
2. Use of a mimic-QHSC-miRNA of claim 1 for the preparation of a medicament for the prevention and/or treatment of hepatocellular carcinoma.
3. The use according to claim 2, wherein the medicament is a medicament which acts directly on liver cancer cells to down-regulate proliferation of the cancer cells.
4. The use according to claim 2, wherein the medicament is a medicament for improving the immune microenvironment of a hepatocellular carcinoma tumor.
5. The use according to claim 2, wherein the medicament is a medicament that significantly induces macrophage polarization.
6. An anti-tumor product, wherein the active ingredient of the product is the mimic-QHSC-miRNA of claim 1; the product is a medicine, an additive or an active ingredient agent; the uses of the product include at least one of the following uses:
(1) Inhibit proliferation of liver cancer cells;
(2) Inducing macrophage polarization to improve tumor immunity microenvironment;
(3) Inhibit the occurrence/development of liver cancer.
7. A pharmaceutical composition for preventing and/or treating hepatocellular carcinoma, comprising the mimic-QHSC-miRNA of claim 1 and a pharmaceutically acceptable adjuvant.
8. The pharmaceutical composition of claim 7, wherein the adjuvant comprises one or more of a diluent, excipient, filler, binder, wetting agent, disintegrant, absorption enhancer, surfactant, adsorption carrier, and lubricant.
9. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is in an oral or non-oral dosage form.
10. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is a tablet, capsule, powder, pill, granule, solution, suspension, syrup, injection, suppository, inhalant or spray.
CN202310792338.4A 2023-06-30 2023-06-30 Mimic-QHSC-miRNA for preventing and/or treating hepatocellular carcinoma and application thereof Pending CN116814625A (en)

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