Mir-34a Derived From Mesenchymal Stem Cells Stimulates Senescence In Glioma Cells By Inducing Dna Damage

Insights into the roles of microRNAs (miRNAs/miRs) in development and disease, particularly in cancer, have made miRNAs attractive tools and targets for novel therapeutic approaches in the treatment of glioma. miR-34a, as a well-known tumor suppressor miRNA, is closely related with cellular senescence. Mesenchymal stem cells (MSCs) are a major component of the tumor microenvironment and possess the ability to deliver exogenous miRs to glioma cells to exert anti-tumor effects. The present study investigated whether modified MSCs with miR-34a possess an anti-tumor function in glioma cells. A Transwell system was used to co-culture U87 glioma cells and MSCs overexpressing miR-34a, and cell proliferation and senescence assessed. The expression of senescence-related genes p53, Cdkn1a, and Cdkn2c were tested using reverse transcription-quantitative polymerase chain reaction and protein expression levels of sirtuin 1 (SIRT1) and -H2A histone family, member X were detected by western blotting. Telomerase activity of U87 cells was examined using the Telo TAGGG Telomerase PCR ELISA PLUS kit. The results demonstrated that the delivered exogenous miR-34a from MSCs significantly decreased expression of the target gene SIRT1. In addition, the delivered miR-34a decreased the proliferation of glioma cells and provoked the expression of senescence-related genes p53, Cdkn1a, and Cdkn2c. In addition, upregulation of miR-34a induced DNA damage, shortened telomere length and impaired telomerase activity. However, these pro-senescent effects were reversed by forced SIRT1 upregulation. In conclusion, the results demonstrated a novel role for miR-34a, inducing glioma cell senescence, whereas miR-34a modulation of SIRT1, inducing DNA damage, is crucial for miRNA replacement therapy in glioma treatment.