title: MiRNA203 suppresses the expression of protumorigenic STAT1 in glioblastoma to inhibit tumorigenesis.
abstract: MicroRNAs (miRNAs) play critical roles in regulating cancer cell proliferation, migration, survival and sensitivity to chemotherapy. The potential application of using miRNAs for cancer prognosis holds great promise but miRNAs with predictive value remain to be identified and underlying mechanisms of how they promote or suppress tumorigenesis are not completely understood. Here, we show a strong correlation between miR203 expression and brain cancer patient survival. Low miR203 expression is found in subsets of brain cancer patients, especially glioblastoma. Ectopic miR203 expression in glioblastoma cell lines inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by interferon or temozolomide in vitro, and inhibited tumorigenesis in vivo. We further show that STAT1 is a direct functional target of miR203, and miR203 level is negatively correlated with STAT1 expression in brain cancer patients. Knockdown of STAT1 expression mimicked the effect of overexpression of miR203 in glioblastoma cell lines, and inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by IFN or temozolomide in vitro, and inhibited glioblastoma tumorigenesis in vivo. High STAT1 expression significantly correlated with poor survival in brain cancer patients. Mechanistically, we found that enforced miR203 expression in glioblastoma suppressed STAT1 expression directly, as well as that of a number of STAT1 regulated genes. Taken together, our data suggest that miR203 acts as a tumor suppressor in glioblastoma by suppressing the pro-tumorigenic action of STAT1. MiR203 may serve as a predictive biomarker and potential therapeutic target in subsets of cancer patients with low miR203 expression.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.|Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Chuan He
authors.initials: CH
authors.lastname: Yang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.|Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.|Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Sims
authors.affiliation: Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, USA.|Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Cai
authors.affiliation: Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, USA.|Department of Nephrology, Shengjing Hospital of China Medical University, Shenyang, China.
authors.forename: Ping
authors.initials: P
authors.lastname: He
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.|Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Junming
authors.initials: J
authors.lastname: Yue
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Jinjun
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Boop
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.|Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Pfeffer
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.|Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Pfeffer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007372:Interferons / Q000494:pharmacology; D008297:Male; D016688:Mice, Inbred NOD; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D034622:RNA Interference; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000077204:Temozolomide; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C546703:MIRN203 microRNA, human; D035683:MicroRNAs; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D003606:Dacarbazine; D007372:Interferons; D000077204:Temozolomide
keywords: STAT1; apoptosis; glioblastoma; miR203; tumorigenesis