PMID- 30654687 OWN - NLM STAT- MEDLINE DCOM- 20200615 LR - 20200615 IS - 1554-8635 (Electronic) IS - 1554-8627 (Print) IS - 1554-8627 (Linking) VI - 15 IP - 6 DP - 2019 Jun TI - MIR93 (microRNA -93) regulates tumorigenicity and therapy response of glioblastoma by targeting autophagy. PG - 1100-1111 LID - 10.1080/15548627.2019.1569947 [doi] AB - Macroautophagy/autophagy is a natural intracellular process that maintains cellular homeostasis and protects cells from death under stress conditions. Autophagy sustains tumor survival and growth when induced by common cancer treatments, including IR and cytotoxic chemotherapy, thereby contributing to therapeutic resistance of tumors. In this study, we report that the expression of MIR93, noted in two clinically relevant tumor subtypes of GBM, influenced GSC phenotype as well as tumor response to therapy through its effects on autophagy. Our mechanistic studies revealed that MIR93 regulated autophagic activities in GSCs through simultaneous inhibition of multiple autophagy regulators, including BECN1/Beclin 1, ATG5, ATG4B, and SQSTM1/p62. Moreover, two first-line treatments for GBM, IR and temozolomide (TMZ), as well as rapamycin (Rap), the prototypic MTOR inhibitor, decreased MIR93 expression that, in turn, stimulated autophagic processes in GSCs. Inhibition of autophagy by ectopic MIR93 expression, or via autophagy inhibitors NSC (an ATG4B inhibitor) and CQ, enhanced the activity of IR and TMZ against GSCs. Collectively, our findings reveal a key role for MIR93 in the regulation of autophagy and suggest a combination treatment strategy involving the inhibition of autophagy while administering cytotoxic therapy. Abbreviations: ACTB: actin beta; ATG4B: autophagy related 4B cysteine peptidase; ATG5: autophagy related 5; BECN1: beclin 1; CL: classical; CQ: chloroquine diphosphate; CSCs: cancer stem cells; GBM: glioblastoma; GSCs: glioma stem-like cells; HEK: human embryonic kidney; IB: immunoblotting; IF: immunofluorescent staining; IR: irradiation; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MES: mesenchymal; MIR93: microRNA 93; MIRC: a control miRNA; miRNA/miR: microRNA; MTOR: mechanistic target of rapamycin kinase; NSC: NSC185085; PN: proneural; qRT-PCR: quantitative reverse transcription-polymerase chain reaction; Rap: rapamycin; SQSTM1/p62: sequestosome 1; TCGA: the cancer genome atlas; TMZ: temozolomide; WT: wild type; ZIP93: lentiviral miRZIP targeting MIR93; ZIPC: lentiviral miRZip targeting control miRNA. FAU - Huang, Tianzhi AU - Huang T AD - a The Ken & Ruth Devee Department of Neurology, Lou and Jean Malnati Brain Tumor Institute , The Robert H. Lurie Comprehensive Cancer Center, Northwestern Universityd Feinberg School of Medicine , Chicago , IL , USA. FAU - Wan, Xuechao AU - Wan X AD - a The Ken & Ruth Devee Department of Neurology, Lou and Jean Malnati Brain Tumor Institute , The Robert H. Lurie Comprehensive Cancer Center, Northwestern Universityd Feinberg School of Medicine , Chicago , IL , USA. FAU - Alvarez, Angel A AU - Alvarez AA AD - a The Ken & Ruth Devee Department of Neurology, Lou and Jean Malnati Brain Tumor Institute , The Robert H. Lurie Comprehensive Cancer Center, Northwestern Universityd Feinberg School of Medicine , Chicago , IL , USA. FAU - James, C David AU - James CD AD - b Department of Neurological Surgery , Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine , Chicago , IL , USA. FAU - Song, Xiao AU - Song X AD - a The Ken & Ruth Devee Department of Neurology, Lou and Jean Malnati Brain Tumor Institute , The Robert H. Lurie Comprehensive Cancer Center, Northwestern Universityd Feinberg School of Medicine , Chicago , IL , USA. FAU - Yang, Yongyong AU - Yang Y AD - a The Ken & Ruth Devee Department of Neurology, Lou and Jean Malnati Brain Tumor Institute , The Robert H. Lurie Comprehensive Cancer Center, Northwestern Universityd Feinberg School of Medicine , Chicago , IL , USA. FAU - Sastry, Namratha AU - Sastry N AUID- ORCID: 0000-0003-4056-6044 AD - a The Ken & Ruth Devee Department of Neurology, Lou and Jean Malnati Brain Tumor Institute , The Robert H. Lurie Comprehensive Cancer Center, Northwestern Universityd Feinberg School of Medicine , Chicago , IL , USA. FAU - Nakano, Ichiro AU - Nakano I AD - c Department of Neurosurgery , University of Alabama at Birmingham , Birmingham , AL , USA. FAU - Sulman, Erik P AU - Sulman EP AUID- ORCID: 0000-0003-4933-9120 AD - d Department of Radiation Oncology , The University of Texas M. D. Anderson Cancer Center, Department of Radiation Oncology , Houston , TX , USA. FAU - Hu, Bo AU - Hu B AD - a The Ken & Ruth Devee Department of Neurology, Lou and Jean Malnati Brain Tumor Institute , The Robert H. Lurie Comprehensive Cancer Center, Northwestern Universityd Feinberg School of Medicine , Chicago , IL , USA. FAU - Cheng, Shi-Yuan AU - Cheng SY AUID- ORCID: 0000-0003-1737-0588 AD - a The Ken & Ruth Devee Department of Neurology, Lou and Jean Malnati Brain Tumor Institute , The Robert H. Lurie Comprehensive Cancer Center, Northwestern Universityd Feinberg School of Medicine , Chicago , IL , USA. LA - eng GR - R01 NS095634/NS/NINDS NIH HHS/United States GR - R01 NS095642/NS/NINDS NIH HHS/United States GR - R01 NS093843/NS/NINDS NIH HHS/United States GR - T32 CA070085/CA/NCI NIH HHS/United States GR - P50 CA221747/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20190131 PL - United States TA - Autophagy JT - Autophagy JID - 101265188 RN - 0 (Autophagy-Related Proteins) RN - 0 (MIRN93 microRNA, human) RN - 0 (MicroRNAs) RN - W36ZG6FT64 (Sirolimus) RN - YF1K15M17Y (Temozolomide) SB - IM MH - Animals MH - Autophagy/drug effects/*genetics/radiation effects MH - Autophagy-Related Proteins/genetics/*metabolism MH - Glioma/drug therapy/*metabolism/*mortality/radiotherapy MH - HEK293 Cells MH - Humans MH - Mice, Nude MH - MicroRNAs/genetics/*metabolism MH - Neoplastic Stem Cells/drug effects/radiation effects MH - Sirolimus/pharmacology MH - Temozolomide/pharmacology MH - Transplantation, Heterologous PMC - PMC6526840 OTO - NOTNLM OT - Autophagy OT - cancer stem cell OT - glioblastoma OT - glioma subtypes OT - microRNA OT - therapy response EDAT- 2019/01/19 06:00 MHDA- 2020/06/17 06:00 PMCR- 2020/01/31 CRDT- 2019/01/19 06:00 PHST- 2019/01/19 06:00 [pubmed] PHST- 2020/06/17 06:00 [medline] PHST- 2019/01/19 06:00 [entrez] PHST- 2020/01/31 00:00 [pmc-release] AID - 1569947 [pii] AID - 10.1080/15548627.2019.1569947 [doi] PST - ppublish SO - Autophagy. 2019 Jun;15(6):1100-1111. doi: 10.1080/15548627.2019.1569947. Epub 2019 Jan 31.