MSI2-TGF-β/TGF-β R1/SMAD3 positive feedback regulation in glioblastoma.

Abstract

Glioblastoma is the most malignant glioma tumors with inevitable relapse and resistance to chemotherapy; however, the mechanisms driving chemoresistance remain to be fully elucidated. This study is to explore the molecular and cellular mechanisms involving in the chemoresistance of glioblastoma. The expression of musashi (MSI) RNA-binding protein in the tumor tissues and cells of glioblastoma was measured. The effects of MSI2 in epithelial-to-mesenchymal transition (EMT), resistance to temozolomide (TMZ), tumor cell invasion, migration, and proliferation and associated signaling were evaluated. High MSI2 expression was observed in the glioblastoma tissues. Silencing or overexpression of MSI2 significantly affected tumor cells invasion, migration, and proliferation. Silencing of MSI2 expression significantly inhibited O6-methylguanine-DNA methyltransferase (MGMT) expression and tumor growth, and reversed resistance to TMZ in xenograft tumor models. MSI2 expression regulated EMT through activating the transcription factors Snail and the TGFβ R1/SMAD3 signaling. Our study demonstrated a positive feedback loop of MSI2-TGFβ/SMAD3 signaling which activates the EMT and MGMT which may contribute to chemoresistance in glioblastoma. This study also highlights that MSI2 could be a new target for the therapy of glioblastoma.