• Jang-Chun Lin, Jo-Ting Tsai, Tsu-Yi Chao, Hsin-I Ma, Chian-Shiu Chien, and Wei-Hsiu Liu.
• Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taiwan, ROC; Department of Radiation Oncology, Shuang-Ho Hospital, Taipei Medical University, Taiwan, ROC; Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taiwan, ROC.
• Radiother Oncol. 2018 Nov 1; 129 (2): 352-363.

IntroductionGlioblastoma multiforme (GBM) is the most common brain malignancy in adults, and currently available GBM treatments present several unique challenges. It is known that GBM involves cancer stem-like cells (CSCs) and tumor cells that aggressively invade normal brain tissues, and both cell types may cause resistance to radiotherapy (RT) and are thus responsible for therapeutic failure. The radioresistance of GBM cells relies on the efficient activation of the DNA damage response (DDR), but the mechanisms linking this response with stem-cell status and tumor invasion remain unclear.Materials And MethodsWe used irradiation to treat patient-derived GBM (Par) cells and then purified radioresistant GBM (R2M2) cells through two rounds of irradiation and an invasion assay. Musashi-1 (MSI1) is a neural stem-cell marker and key oncogenic factor of GBM. We identified MSI1 expression to predict radioresistance through silencing an MSI1-high-expressing R2M2 cell line or inducing overexpression in a Par cell line with low/no MSI1 expression and assessing the subsequent DDR.ResultMSI1 enhances tumor invasion via VCAM1 and modulates GBM radioresistance via the hyperactivation of the DDR through increasing homologous recombination repair and evading apoptosis. MSI1 knockdown induces DNA damage accumulation in irradiated GBM cells and promotes their depletion in vitro; MSI1 knockdown also inhibits the formation of GBMs generated by irradiated xeno-transplanted cells. MSI1 inhibition may radiosensitize tumors, prevent CSC-positive selection induced by RT, and reduce tumor invasion.ConclusionMSI1 may involve in regulating GBM radioresistance, invasion, and recurrence and could be a novel target for GBM treatment.Copyright © 2018 Elsevier B.V. All rights reserved.

41 keywords...

hide…