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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
- 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.
- Subjects :
- Male
0301 basic medicine
Oncology
Gerontology
medicine.medical_treatment
Apoptosis
Mice
0302 clinical medicine
RNA, Small Interfering
Mice, Inbred BALB C
biology
Brain Neoplasms
RNA-Binding Proteins
chemoresistance
humanities
Cytokine
030220 oncology & carcinogenesis
Signal Transduction
Research Paper
medicine.medical_specialty
Cell Survival
Mice, Nude
Nerve Tissue Proteins
Malignancy
GBM
03 medical and health sciences
Cell Line, Tumor
Internal medicine
medicine
Animals
Humans
Progenitor cell
Interleukin 6
Protein kinase B
Inflammation
IL-6
Interleukin-6
business.industry
Computational Biology
Cancer
medicine.disease
030104 developmental biology
Musashi-1
Drug Resistance, Neoplasm
biology.protein
Cytokine secretion
Neoplasm Recurrence, Local
Glioblastoma
business
Proto-Oncogene Proteins c-akt
Neoplasm Transplantation
Subjects
Details
- ISSN :
- 19492553
- Volume :
- 7
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....79bb6d1185e44e2007e991121edafef6
- Full Text :
- https://doi.org/10.18632/oncotarget.9890