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

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.

Transforming Growth Factor-Beta-Regulated LncRNA-MUF Promotes Invasion by Modulating the miR-34a Snail1 Axis in Glioblastoma Multiforme

“…TGF-β-induced lncRNAs are known to regulate the TGF-β signaling pathway via an autocrine signaling loop ( 33 ). Hence, we asked if lncRNA-MUF is also involved in regulating TGF-β signaling.…”

“…In line with these findings, we show that lncRNA-MUF induction by TGF-β is completely abrogated upon treatment with TGFβR1/smad 2/3 inhibitor SB505124 in glioma cells ( Figure 2C ). TGF-β-regulated lncRNA-MIR100HG regulates smad2/3 phosphorylation in prostate carcinoma ( 33 ). LncRNA-MUF also regulates the TGF-β signaling by preventing the SMAD4 degradation by competing with β-TrCP in CRC ( 39 ).…”

Transforming growth factor β latency: A mechanism of cytokine storage and signalling regulation in liver homeostasis and disease

“… Molecules/compounds Function Ref. MIR100HG Long noncoding RNA, controls the magnitude of TGF-β signalling in carcinomas 59 GM6001 Metalloprotease inhibitor, abrogates αvβ8-mediated TGF-β activation in airway fibroblasts and SW480 cells 86 , 98 c8 Synthetic compound with inhibitory activity on αvβ1 integrin and downstream L-TGF-β activation in fibroblasts 103 CWHM12 Small molecule inhibitor of αv integrins, potential anti-fibrotic effects 105 LSKL Peptide that blocks TSP-1-mediated TGF-β signalling activation 118 KRFK TSP-1-derived TGF-β1 activating peptide 118 NDMA Organic chemical, induction of hepatic fibrosis in mouse model 131 LAP-DP Valuable biomarkers for monitoring L-TGF-β activation and the clinical course of chronic liver diseases 139 cRGD Synthetic peptide blocking the interaction of αv integrin and L-TGF-β 182 LAP, latency-associated peptide; LAP-DP, LAP degradation product; L-TGF-β, latent TGF-β; NDMA, N-nitrosodimethylamine; TGF-β, transforming growth factor β; TSP-1, thrombospondin 1. …”

“… 58 Additionally, a long noncoding RNA, MIR100HG, induced by TGF-β, facilitates L-TGF-β1 secretion and controls the magnitude of TGF-β signalling, especially in carcinomas. 59 …”

Promotion or remission: a role of noncoding RNAs in colorectal cancer resistance to anti-EGFR therapy

“…MIR100HG, encoded by the MIR100HG gene on chromosome 11 [ 148 ], is upregulated in Cetuximab-resistant CRC cells [ 41 ]. Liu et al .…”