Glioblastoma multiforme (GBM) is characterized by diffuse infiltration of the brain, active regional recurrence, low cure proportion, and limited chemotherapy efficiency. MutS homolog 6 (MSH6) is a component of the mismatch repair system related to the oncogenesis, tumor evolution, and recurrence of GBM. The impact of MSH6 upregulation on the tumor microenvironment (TME) of GBM and the feasibility of MSH6 as a potential target to improve the prognosis remain unknown. The expression of MSH6 at mRNA level indicated that MSH6 expressed higher in GBM tissues than that in normal ones. The transwell assay and expression levels of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) suggested that the capability of invasion and migration in U251-MSH6 was more stubborn. The intracranial tumor model was established with nude mice to further explore in vivo. The time-weight curve, overall survival, tumor volumes, expression levels of MMP-2 and MMP-9 in tissue, and hematoxylin and eosin staining all indicated that MSH6 had a positive effect on metastasis. The expression levels of related proteins suggested that the hypoxia TME induced by MSH6 may promote metastasis via epithelial to mesenchymal transition, stemness, and angiogenesis progress. MSH6 is an overexpressed oncogene in human GBM tissues, which accelerated metastasis by regulating hypoxia inducible factor-1A (HIF1A) to form a hypoxic TME in GBM. The MSH6 was a vital marker of GBM, making it a promising therapeutic target.
Keywords: HIF1A; MSH6; glioblastoma multiforme; hypoxia; tumor microenvironment.