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Musashi-1 regulates AKT-derived IL-6 autocrinal/paracrinal malignancy and chemoresistance in glioblastoma

Musashi-1 regulates AKT-derived IL-6 autocrinal/paracrinal malignancy and chemoresistance in glioblastoma

Authors :
Tzu Chien Chen
Shih Hwa Chiou
Chi Chang Tsai
Wei Hsiu Liu
Yi Ping Yang
Pin I. Huang
Liang Ting Lin
Yi Wei Chen
Ming Long Tsai
Yuh Lih Chang
Wen Liang Lo
Yi Yen Lee
Shu Hsien Lee
Hsiao Yun Chen
Ming Teh Chen
Mong Lien Wang
Source :
Oncotarget
Publication Year :
2016
Publisher :
Impact Journals, LLC, 2016.

Abstract

// Hsiao-Yun Chen 1 , Liang-Ting Lin 2, * , Mong-Lien Wang 2, * , Shu-Hsien Lee 2, * , Ming-Long Tsai 1 , Chi-Chang Tsai 2 , Wei-Hsiu Liu 4 , Tzu-Chien Chen 5 , Yi-Ping Yang 1, 4 , Yi-Yen Lee 1, 8 , Yuh-Lih Chang 2, 5 , Pin-I Huang 1, 6 , Yi-Wei Chen 1, 6 , Wen-Liang Lo 1, 7 , Shih-Hwa Chiou 1, 2, 3, 5 , Ming-Teh Chen 1, 3,8 1 Institute of Clinical Medicine, National Yang-Ming University, Taipei Veterans General Hospital, Taipei, Taiwan 2 Institute of Pharmacology, National Yang-Ming University, Taipei Veterans General Hospital, Taipei, Taiwan 3 School of Medicine, National Yang-Ming University, Taipei Veterans General Hospital, Taipei, Taiwan 4 Graduate Institute of Medical Sciences, National Defense Medical Center, Department of Neurological Surgery, Taipei Veterans General Hospital, Taipei, Taiwan 5 Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan 6 Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan 7 Division of Oral and Maxillofacial Surgery, Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan 8 Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan * These authors have contributed equally to this work Correspondence to: Shih-Hwa Chiou, email: shchiou@vghtpe.gov.tw Ming-Teh Chen, email: mtchen@vghtpe.gov.tw Keywords: Musashi-1, apoptosis, IL-6, chemoresistance, GBM Received: October 14, 2015 Accepted: May 11, 2016 Published: June 7, 2016 ABSTRACT Glioblastoma multiform (GBM) is one of the most lethal human malignant brain tumors with high risks of recurrence and poor treatment outcomes. The RNA-binding protein Musashi-1 (MSI1) is a marker of neural stem/progenitor cells. Recent study showed that high expression level of MSI1 positively correlates with advanced grade of GBM, where MSI1 increases the growth of GBM. Herein, we explore the roles of MSI1 as well as the underlying mechanisms in the regulation of drug resistance and tumorigenesis of GBM cells. Our results demonstrated that overexpression of MSI1 effectively protected GBM cells from drug-induced apoptosis through down-regulating pro-apoptotic genes; whereas inhibition of AKT withdrew the MSI1-induced anti-apoptosis and cell survival. We further showed that MSI1 robustly promoted the secretion of the pro-inflammatory cytokine IL-6, which was governed by AKT activity. Autonomously, the secreted IL-6 enhanced AKT activity in an autocrine/paracrine manner, forming a positive feedback regulatory loop with the MSI1-AKT pathway. Our results conclusively demonstrated a novel drug resistance mechanism in GBM cells that MSI1 inhibits drug-induced apoptosis through AKT/IL6 regulatory circuit. MSI1 regulates both cellular signaling and tumor-microenvironmental cytokine secretion to create an intra- and intercellular niche for GBM to survive from chemo-drug attack.

Details

ISSN :
19492553
Volume :
7
Database :
OpenAIRE
Journal :
Oncotarget
Accession number :
edsair.doi.dedup.....79bb6d1185e44e2007e991121edafef6
Full Text :
https://doi.org/10.18632/oncotarget.9890