Tumor-associated miRNA and its clinical application in tumor miRNA therapy

MicroRNA (mirna; MiR) is closely related to the occurrence and development of tumors, and is abnormally expressed in many tumors. Controlling the expression of cancer-related miRNAs is expected to become a new generation of drug models for the treatment of advanced cancer.

In June, 20021,researchers from Japan published a review article in the Journal of Human Genetics, summarizing tumor-associated mirnas related to various cancer pathologies and their clinical application in cancer mirna treatment.

Many studies have shown that in many cancer types, the abnormal expression of miRNAs is caused by gene distortion (including genetic and epigenetic changes), and plays a role in the occurrence and development of cancer through the imbalance of target gene expression. Therefore, many miRNAs are closely related to the pathogenesis of tumors, including cell proliferation, cell survival and cell invasion.

The abnormally high expression of OncomiR in tumor directly binds to several tumor suppressor genes, and down-regulates the expression of these mRNA, thus leading to the growth, migration and metastasis of cancer cells. Therefore, functional inhibition of OncomiR is an effective cancer treatment strategy.

Introducing synthetic anti-miR complementary to OncomiR into cancer cells can prevent OncomiR from combining with target RNA, thus inhibiting the proliferation and metastasis of cancer cells. For example, Viridian therapeutics developed an anti-Mir: MRG- 106 (Cobomarsen) which is complementary to miR- 155, and conducted a phase I clinical trial of intratumoral administration of MRG- 106 to patients with cutaneous T-cell lymphoma (ClinicalTrials.gov identifier NCT 02580552).

Contrary to OncomiR, the abnormally low expression of TS-miR in tumors plays a role in the occurrence and malignant progress of tumors by avoiding the down-regulation of many oncogenes. Through the functional screening of human miRNA library and the analysis of miRNA expression, the research team found a number of TS-miRs involved in various cancer pathological processes.

Because TS-miR can inhibit the expression of many oncogenes at the same time, it is considered to be a therapeutically reasonable method to introduce the synthetic double-stranded (ds)-TS-miR mimetic into the replacement therapy of cancer cells. The research team studied miR-634.

1) firstly, the potential of ds-miR-634 mimetic as an anticancer drug was confirmed in vitro. The introduction of ds-miR-634 mimetic significantly increased the sensitivity of several cancer cell lines, including esophageal squamous cell carcinoma (ESCC) cells, and confirmed that in the mouse model of ESCC xenotransplantation, the local injection of ds-miR-634 mimetic into the subcutaneous space around the tumor increased cisplatin.

2) Next, the research team developed a kind of lipid nanoparticles (LNP) (provided by Weicai Co., Ltd.), which contained a synthetic ds-miR-634 mimic (miR-634-LNP) and conducted animal experiments. In the mouse model of pancreatic cancer xenotransplantation, miR-634-LNP was injected into the tail vein to deliver miR-634 to tumor cells effectively and inhibit the expression of target gene. Compared with the control group, mice taking miR-634-LNP have obvious anti-tumor effect. This indicates that LNP-mediated delivery of miR-634 is a potentially useful cancer treatment strategy.

3) Recently, the research team used ionic liquid technology (ILTS? MEDRx, Co.Ltd) prepared ointment containing ds-miR-634 mimetic. In the mouse model of skin squamous cell carcinoma (cSCC) xenotransplantation and carcinogen-induced papilloma, local application of miR-634 ointment inhibited tumor growth in vivo without toxicity. The forced expression of miR-634 induces high-energy stress by inhibiting various cell protection processes, including autophagy, antioxidant scavenging, anti-apoptosis and glutamine decomposition, thus synergistically enhancing EGFR-TKI-induced cytotoxicity. Therefore, the research team believes that local application of miR-634 ointment is a reasonable strategy to improve the efficacy of EGFR-TKI in the treatment of cSCC by inhibiting multiple cell protection processes at the same time.

MetastamiR promotes or inhibits tumor metastasis by directly targeting genes involved in cancer cell migration, invasion, settlement, tumor stem cells and epithelial-mesenchymal transition (EMT). For example, a nanoparticle preparation containing anti-mir-10b (TTX-MC138) developed by TransCode Therapeutics Company was systematically applied to mice, which significantly inhibited the experimental metastasis of several cancers, including breast cancer, lung cancer and pancreatic cancer. In addition, controlling the expression of MetastamiRs may lead to the development of new therapeutic strategies to inhibit the migration and invasion of cancer cells and tumor metastasis.

Angiogenesis plays an important role in the growth, survival and metastasis of tumor cells in tumor microenvironment and is a potential therapeutic target. The expression of angiogenesis-related miRNA(AngiomiRs) in vascular endothelial cells promotes angiogenesis in tumor tissues by regulating cytokine signals, metalloproteinases, vascular endothelial growth factor signals and platelet-derived growth factor signals. In addition, immune mirs involved in tumor immune system can promote tumor cells to escape immune surveillance by regulating inflammatory signals and factors in NF-kB pathway in tumor microenvironment. Therefore, therapeutic control of the expression of vascular miRs or immune miRs in tumor microenvironment may become a new therapeutic method to inhibit angiogenesis or improve the effect of tumor immunotherapy.

More and more evidences show that the synthesized ds-TS-miR mimetic is an effective cancer treatment strategy, because it can simultaneously inhibit multiple pathways involved in cancer progression. Different from traditional molecular targeted drugs and antibody drugs that control one molecule, TS-miR replacement therapy can control the expression of multiple oncogenes at the same time. Another advantage of miRNA therapy is that TS-miR can be synthesized and prepared in a short time. In the future, the synthesis of nucleic acid by chemical modification and the optimization of drug delivery system (DDS) are expected to rapidly promote the development of miRNA therapy.

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refer to

Cancer-related microRNA and its therapeutic potential. ? J Hum Genet(202 1)。 https://doi . org/ 10. 1038/s 10038-02 1-00938-6