MicroRNA-34a-5p suppresses tumorigenesis and progression of glioma and potentiates Temozolomide-induced cytotoxicity for glioma cells by targeting HMGA2

Abstract

Glioma is a frequently diagnosed brain tumors and Temozolomide (TMZ) is a common chemotherapeutic drug for glioma. High mobility group AT-hook 2 (HMGA2) was reported to be linked with glioma pathogenesis and Temozolomide (TMZ)-induced cytotoxicity. Our present study aimed to further search for the upstream regulatory microRNAs (miRNAs) of HMGA2 in glioma. RT-qPCR assay was conducted to measure the expression of HMGA2 mRNA and microRNA-34a-5p (miR-34a-5p). HMGA2 protein expression was examined by western blot assay. Cell proliferative ability and cell viability was assessed by CCK-8 assay. Cell migratory and invasive capacities were estimated by Transwell migration and invasion assay. Bioinformatics analysis and luciferase reporter assay was conducted to investigate the potential interaction between miR-34a-5p and HMGA2. Mouse xenograft experiments were performed to further test the roles of TMZ, miR-34a-5p and HMGA2, alone or in combination, in glioma tumorigenesis in vivo. We found HMGA2 expression was notably upregulated in glioma tissues and cells, and associated with glioma grade and poor prognosis. HMGA2 knockdown or miR-34a-5p overexpression inhibited migration, invasion, proliferation and enhanced TMZ-induced cytotoxicity in glioma cells. Moreover, HMGA2 was a target of miR-34a-5p. And, miR-34a-5p expression was remarkably reduced in glioma tissues and cells. MiR-34a-5p exerted its function through targeting HMGA2 in glioma cells. HMGA2 knockdown or miR-34a-5p overexpression inhibited tumor growth and enhanced TMZ-mediated anti-tumor effect in glioma xenograft models. We concluded MiR-34a-5p suppressed tumorigenesis and progression of glioma and potentiated TMZ-induced cytotoxicity for glioma cells by targeting HMGA2, deepening our understanding on molecular basis of HMGA2 in glioma.