miR‑34a derived from mesenchymal stem cells stimulates senescence in glioma cells by inducing DNA damage

Li,Qun; Wang,Chengde; Cai,Lin; Lu,Jianglong; Zhu,Zhangzhang; Wang,Chunyong; Su,Zhipeng; Lu,Xianghe

doi:10.3892/mmr.2018.9800

miR‑34a derived from mesenchymal stem cells stimulates senescence in glioma cells by inducing DNA damage

Authors:
- Qun Li
- Chengde Wang
- Lin Cai
- Jianglong Lu
- Zhangzhang Zhu
- Chunyong Wang
- Zhipeng Su
- Xianghe Lu
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Affiliations: Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
Published online on: December 24, 2018 https://doi.org/10.3892/mmr.2018.9800
Pages: 1849-1857

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Abstract

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 γ‑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.

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