The noncoding MIR100HG RNA enhances the autocrine function of transforming growth factor β signaling
Open Access
- 4 May 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 40 (21), 3748-3765
- https://doi.org/10.1038/s41388-021-01803-8
Abstract
Activation of the transforming growth factor β (TGFβ) pathway modulates the expression of genes involved in cell growth arrest, motility, and embryogenesis. An expression screen for long noncoding RNAs indicated that TGFβ induced mir-100-let-7a-2-mir-125b-1 cluster host gene (MIR100HG) expression in diverse cancer types, thus confirming an earlier demonstration of TGFβ-mediated transcriptional induction of MIR100HG in pancreatic adenocarcinoma. MIR100HG depletion attenuated TGFβ signaling, expression of TGFβ-target genes, and TGFβ-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 TGFβ signaling responses. Screening for downstream effectors of MIR100HG identified the ligand TGFβ1. MIR100HG and TGFB1 mRNA formed ribonucleoprotein complexes with the RNA-binding protein HuR, promoting TGFβ1 cytokine secretion. In addition, TGFβ 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 TGFβ/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 TGFβ induces MIR100HG, which then enhances TGFβ1 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 TGFβ signaling via TGFβ1 autoinduction and secretion in carcinomas.This publication has 35 references indexed in Scilit:
- A conserved TGFβ1/HuR feedback circuit regulates the fibrogenic response in fibroblastsCellular Signalling, 2012
- The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics DataCancer Discovery, 2012
- RNAscope: A Novel in Situ RNA Analysis Platform for Formalin-Fixed, Paraffin-Embedded TissuesThe Journal of Molecular Diagnostics, 2012
- Non-coding RNAs in human diseaseNature Reviews Genetics, 2011
- MicroRNAs and the cell cycleBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2011
- The Myc–miR-17∼92 Axis Blunts TGFβ Signaling and Production of Multiple TGFβ-Dependent Antiangiogenic FactorsCancer Research, 2010
- Glycogene Expression Alterations Associated with Pancreatic Cancer Epithelial-Mesenchymal Transition in Complementary Model SystemsPLOS ONE, 2010
- Smad Proteins Bind a Conserved RNA Sequence to Promote MicroRNA Maturation by DroshaMolecular Cell, 2010
- Mechanism of TGF-β signaling to growth arrest, apoptosis, and epithelial–mesenchymal transitionCurrent Opinion in Cell Biology, 2009
- Cloning and Characterization of HuR, a Ubiquitously Expressed Elav-like ProteinOnline Journal of Public Health Informatics, 1996