The Role Of MiR-127-3p In Glioblastoma And Its Molecular Mechanism

MicroRNAs (miRNAs) are small non-coding RNAs of20-25nucleotides in length which are capable of modulating gene expression post-transcriptionally by interacting with complementary sites in the3’untranslated region(3’UTR). MiRNAs are involved in many physiological and pathological processes and are emerging as important modulators of cellular signaling, including cell proliferation and metastasis in cancer. Gliomas are the most prevalent brain tumors of glial origin. Despite recent advances in diagnostics and treatments, prognosis for advanced patients remains poor. The median survival is only12to15months for glioblastoma (GBM). The tumorigenesis of GBM is a multistep process during which the expression levels of many factors are altered, among them, the potential roles of miRNAs have been under intensive studies in the past few years.In the first section, we found that miR-127-3p was downregulated in GBM tissues compared with normal brain tissues using next generation sequencing analysis of miRNAs, and we validated this result by RT-PCR. We further showed that DNA demethylation and histone deacetylase inhibition resulted in downregulation of miR-127-3p. We demonstrated that miR-127-3p overexpression inhibited GBM cell growth by inducing G1-phase arrest both in vitro and in vivo. We showed that miR-127-3p targeted SKI (v-ski sarcoma viral oncogene homolog [avian]), RGMA (RGM domain family, member A), ZWINT (ZW10interactor, kinetochore protein), SERPINB9(serpin peptidase inhibitor, clade B [ovalbumin], member9) and SFRP1 (secreted frizzled-related protein1). Finally, we found that miR-127-3p suppress GBM cell growth by inhibiting tumor-promoting SKI and activating the tumor suppression effect of transforming growth factor-β (TGF-B) signaling. To the best of our knowledge, the role of SKI in glioma has not yet been studied. The current study provides the first evidence that SKI plays a role in GBM.In the second section, we found that the level of miR-127-3p and cell migration and invasion in several human GBM cell lines were positively correlated. We showed that miR-127-3p promoted cell migration and invasion of GBM cells using in vitro cell lines and in vivo mouse models. We identified SEPT7, a known tumor suppressor gene that has been reported to suppress GBM cell migration and invasion, as a direct target of miR-127-3p. SEPT7was able to abrogate the effect of miR-127-3p on cell migration and invasion partially. In addition, a microarray analysis revealed that miR-127-3p could regulate many migration and invasion related genes. Finally, we verified miR-127-3p affected the remodeling of the F-actin cytoskeleton mediated by SEPT7in GBM cells.Our study shows that miR-127-3p is a key factor in GBM, and we also indicated that miR-127-3p may be a potential target for GBM therapy.