The noncoding MIR100HG RNA enhances the autocrine function of transforming growth factor beta signaling

Autor: Papoutsoglou, Panagiotis, Rodrigues Junior, Dorival Mendes, Morén, Anita, Bergman, Andrew, Pontén, Fredrik, Coulouarn, Cedric, Caja, Laia, Heldin, Carl-Henrik, Moustakas, Aristidis
Přispěvatelé: Uppsala University, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Cancerfonden Swedish Cancer Society [CAN2012/438, CAN2015/438, CAN2018/469], Vetenskapsradet Swedish Research Council [K2013-66X-14936-10-5, 2017-01588-3, 2018-02757-3, 2015-02757, 2020-01291], Barncancerfonden [PR2018-0091], European Research Council European Research Council (ERC) European Commission [787472], Bodossaki Foundation, Alexander Onassis Foundation, Greece, Inserm Institut National de la Sante et de la Recherche Medicale (Inserm) European Commission, Universite de Rennes-1, ITMO Cancer AVIESAN Plan Cancer [C18007NS], Ludwig Cancer Research, Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Jonchère, Laurent
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Oncogene
Oncogene, 2021, 40 (21), pp.3748-3765. ⟨10.1038/s41388-021-01803-8⟩
Oncogene, Nature Publishing Group, 2021, 40 (21), pp.3748-3765. ⟨10.1038/s41388-021-01803-8⟩
ISSN: 0950-9232
1476-5594
Popis: Activation of the transforming growth factor beta (TGF beta) pathway modulates the expression of genes involved in cell growth arrest, motility, and embryogenesis. An expression screen for long noncoding RNAs indicated that TGF beta induced mir-100-let-7a-2-mir-125b-1 cluster host gene (MIR100HG) expression in diverse cancer types, thus confirming an earlier demonstration of TGF beta-mediated transcriptional induction of MIR100HG in pancreatic adenocarcinoma. MIR100HG depletion attenuated TGF beta signaling, expression of TGF beta-target genes, and TGF beta-mediated cell cycle arrest. Moreover, MIR100HG silencing inhibited both normal and cancer cell motility and enhanced the cytotoxicity of cytostatic drugs. MIR100HG overexpression had an inverse impact on TGF beta signaling responses. Screening for downstream effectors of MIR100HG identified the ligand TGF beta 1. MIR100HG and TGFB1 mRNA formed ribonucleoprotein complexes with the RNA-binding protein HuR, promoting TGF beta 1 cytokine secretion. In addition, TGF beta regulated let-7a-2-3p, miR-125b-5p, and miR-125b-1-3p expression, all encoded by MIR100HG intron-3. Certain intron-3 miRNAs may be involved in TGF beta/SMAD-mediated responses (let-7a-2-3p) and others (miR-100, miR-125b) in resistance to cytotoxic drugs mediated by MIR100HG. In support of a model whereby TGF beta induces MIR100HG, which then enhances TGF beta 1 secretion, analysis of human carcinomas showed that MIR100HG expression correlated with expression of TGFB1 and its downstream extracellular target TGFBI. Thus, MIR100HG controls the magnitude of TGF beta signaling via TGF beta 1 autoinduction and secretion in carcinomas.
Databáze: OpenAIRE
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