Mechanism Research Of Microrna And Antitumor Activity Of Novel Aptamer-targeted Nanoparticles Based On Microrna

MicroRNAs(miRNAs) are single-stranded non-coding RNA molecules of 20-25 nucleotides, which bind to the 3’-untranslated region(3’-UTR) of m RNA through partial base-pairing and result in degradation and translation suppression of their target mRNA. A single miRNA can target multiple genes due to the imperfect complementation with target m RNA, while the expression of a single gene can be modulated by different miRNAs. The dysregulation of miRNA expression has been found to be closely associated with carcinogenesis and mi RNAs function as tumor suppressors or oncogenes during tumor initiation and progression.Hsa-mi R-124(miR-124) was found to be significantly down-regulated in a number of tumors, including cervical cancer which is the second most common malignant tumor in women around the world. To explore the biological functions of miR-124 in cervical cancer, miR-124 expressing vector was constructed and stably transfected in cervical cancer cells. We found that exogenous expression of miR-124 could significantly suppress the proliferation, migration and invasion of cervical cancer cells. We further found that the expression of CUB domain containing protein 1(CDCP1) was remarkably down-regulated in miR-124 transfected cervical cancer cells. The results of luciferase assay showed that Cdcp1 is a direct down-stream target of miR-124. To explore whether Cdcp1 is involved in tumor suppressive functions of miR-124, Cdcp1 was exogenously expressed in miR-124-transfected cells and the results showed that Cdcp1 expression counteracted the tumor suppressive effects of miR-124. The restoration of Cdcp1 in miR-124-transfected cells increased the migration and invasion of cervical cells, indicating that mi R-124 suppressed cervical cancer cell motility through targeting Cdcp1 gene.Numerous evidences show that miRNAs may have a great potential in cancer therapy. Lung cancer is a leading disease with high cancer-related prevalence and mortality. At present, nanoparticle-based targeted cancer therapy has been attracted a great attention in cancer treatment. In this study, a targeted delivery carrier of mi RNA was established based on protamine-functionalized nanodiamonds. Negatively charged mi R-34 a was attached on the surface of positive charged protamine-functionalized nanodiamonds and further coupled with a MUC-1 aptamer to construct aptamer-directed nanocomplexes for targeted tumor therapy. The results showed that miR-34 a can be efficiently delivered into NSCLC cells and the aptamer-mi RNA chimeras can be used as an effective targeting agent for selective intracellular delivery of tumor-suppressor mi RNA. The expression of miR-34 a was widely down-regulated in a number of tumors including lung cancer. The remarkable restoration of miR-34 a significantly suppressed the migration of NSCLC cells and induced cell apoptosis via targeting SirT1 signaling pathway. This study suggests that MUC-1 aptamer-directed protamine-functionalized nanodiamonds have a great potential as a delivery system for targeted miRNA-based tumor therapy.