in June, 221, researchers from Japan published a review article in Journal of Human Genetics, summarizing tumor-related miRNAs related to various cancer pathologies and their clinical applications in cancer mirna treatment.
many studies have shown that the abnormal expression of miRNAs is caused by gene aberrations (including genetic and epigenetic changes) in many cancer types, 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 cancer can directly bind to several tumor suppressor genes and down-regulate 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 binding to target RNA, thus inhibiting the proliferation and metastasis of cancer cells. For example, Viridian therapeutics Company developed an anti-Mir: MRG-16 (Cobomarsen) which is complementary to miR-155, and conducted a phase I clinical trial of intratumoral administration of MRG-16 to patients with cutaneous T-cell lymphoma (ClinicalTrials.gov Identifier NCT 258552).
contrary to OncomiR, the abnormally low expression of TS-miR in tumor plays a role in the occurrence and malignant progress of tumor by escaping the down-regulation of many oncogenes. Through the functional screening of human miRNA library and the expression analysis of miRNAs, 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 synthetic double-stranded (ds)-TS-miR mimics into the replacement therapy of cancer cells. The research team conducted research on miR-634.
1) firstly, it confirmed the potential of ds-miR-634 mimetic as an anticancer drug 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 the local injection of ds-miR-634 mimetic into the subcutaneous space around the tumor increased the anti-tumor effect of cisplatin in the mouse model of ESCC xenotransplantation.
2) next, the research team developed a lipid nanoparticle (LNP) (provided by Eisai 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, so that miR-634 was effectively delivered to tumor cells and the expression of target gene was inhibited. Compared with the control group, mice taking miR-634-LNP had 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 an ointment containing ds-miR-634 mimetic. In the mouse models 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 the local application of miR-634 ointment is a reasonable strategy to improve the efficacy of EGFR-TKI in treating cSCC by simultaneously inhibiting multiple cell protection processes.
MetastamiR promotes or inhibits tumor metastasis by directly targeting genes involved in cancer cell migration, invasion, colonization, tumor stem cells and epithelial-mesenchymal transition (EMT). For example, the nano-particle preparation containing anti-miR-1b(TTX-MC138) developed by TransCode Therapeutics Company was systematically administered 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 it 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, which participate 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, therapeutically controlling the expression of AngiomiRs or Immuno-miRs in tumor microenvironment may be a new therapeutic method to inhibit angiogenesis in tumor microenvironment or improve the effect of tumor immunotherapy.
More and more evidences show that the synthetic 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 needed for preparation can be synthesized in a short time. In the future, the development of miRNA therapy is expected to advance rapidly by synthesizing nucleic acid through chemical modification and optimizing drug delivery system (DDS).
initial public number: national gene bank big data platform
references
inoue, J., Inazawa, J. Cancer-associated mirnas and their therapeutic potential. J Hum Genet(221). https://doi.org/1.138/s138-21-938-6