Oncotarget

Research Papers:

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

Hsiao-Yun Chen, Liang-Ting Lin, Mong-Lien Wang, Shu-Hsien Lee, Ming-Long Tsai, Chi-Chang Tsai, Wei-Hsiu Liu, Tzu-Chien Chen, Yi-Ping Yang, Yi-Yen Lee, Yuh-Lih Chang, Pin-I Huang, Yi-Wei Chen, Wen-Liang Lo, Shih-Hwa Chiou _ and Ming-Teh Chen

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Oncotarget. 2016; 7:42485-42501. https://doi.org/10.18632/oncotarget.9890

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Abstract

Hsiao-Yun Chen1, Liang-Ting Lin2,*, Mong-Lien Wang2,*, Shu-Hsien Lee2,*, Ming-Long Tsai1, Chi-Chang Tsai2, Wei-Hsiu Liu4, Tzu-Chien Chen5, Yi-Ping Yang1,4, Yi-Yen Lee1,8, Yuh-Lih Chang2,5, Pin-I Huang1,6, Yi-Wei Chen1,6, Wen-Liang Lo1,7, Shih-Hwa Chiou1,2,3,5, Ming-Teh Chen1,3,8

1Institute of Clinical Medicine, National Yang-Ming University, Taipei Veterans General Hospital, Taipei, Taiwan

2Institute of Pharmacology, National Yang-Ming University, Taipei Veterans General Hospital, Taipei, Taiwan

3School of Medicine, National Yang-Ming University, Taipei Veterans General Hospital, Taipei, Taiwan

4Graduate Institute of Medical Sciences, National Defense Medical Center, Department of Neurological Surgery, Taipei Veterans General Hospital, Taipei, Taiwan

5Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan

6Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan

7Division of Oral and Maxillofacial Surgery, Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan

8Department 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.


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