Cysteine-rich 61-Connective Tissue Growth Factor-nephroblastoma-overexpressed 5 (CCN5)/Wnt-1-induced Signaling Protein-2 (WISP-2) Regulates MicroRNA-10b via Hypoxia-inducible Factor-1α-TWIST Signaling Networks in Human Breast Cancer Cells

Inamul Haque,Snigdha Banerjee,Smita Mehta,Archana De,Monami Majumder,Matthew S Mayo,Suman Kambhampati,Donald R Campbell,Sushanta K Banerjee

doi:10.1074/jbc.m111.284158

Inamul Haque, Snigdha Banerjee + Show 7 more

Open Access

https://doi.org/10.1074/jbc.m111.284158

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Abstract

MicroRNAs (miRNAs) are naturally occurring single-stranded RNA molecules that post-transcriptionally regulate the expression of target mRNA transcripts. Many of these target mRNA transcripts are involved in regulating processes commonly altered during tumorigenesis and metastatic growth. These include cell proliferation, differentiation, apoptosis, migration, and invasion. Among the several miRNAs, miRNA-10b (miR-10b) expression is increased in metastatic breast cancer cells and positively regulates cell migration and invasion through the suppression of the homeobox D10 (HOXD10) tumor suppressor signaling pathway. In breast metastatic cells, miR-10b expression is enhanced by a transcription factor TWIST1. We find that miR-10b expression in breast cancer cells can be suppressed by CCN5, and this CCN5 effect is mediated through the inhibition of TWIST1 expression. Moreover, CCN5-induced inhibition of TWIST1 expression is mediated through the translational inhibition/modification of hypoxia-inducible factor-1α via impeding JNK signaling pathway. Collectively, these studies suggest a novel regulatory pathway exists through which CCN5 exerts its anti-invasive function. On the basis of these findings, it is plausible that reactivation of CCN5 in miR-10b-positive invasive/metastatic breast cancers alone or in combination with current therapeutic regimens could provide a unique, alternative strategy to existing breast cancer therapy.

Highlights

Because CCN5 is an anti-invasive gene, present studies were designed to determine whether CCN5 exerts its anti-invasive function through controlling microRNA-10b expression
We find that miR-10b expression in breast cancer cells can be suppressed by CCN5, and this CCN5 effect is mediated through the inhibition of TWIST1 expression
The present study reveals that miR-10b expression in breast cancer cells is regulated by extracellular protein CCN5/WISP-2

Summary

Introduction

Because CCN5 is an anti-invasive gene, present studies were designed to determine whether CCN5 exerts its anti-invasive function through controlling microRNA-10b expression. MicroRNAs (miRNAs) are naturally occurring singlestranded RNA molecules that post-transcriptionally regulate the expression of target mRNA transcripts. Many of these target mRNA transcripts are involved in regulating processes commonly altered during tumorigenesis and metastatic growth. Among the several miRNAs, miRNA10b (miR-10b) expression is increased in metastatic breast cancer cells and positively regulates cell migration and invasion through the suppression of the homeobox D10 (HOXD10) tumor suppressor signaling pathway. CCN5-induced inhibition of TWIST1 expression is mediated through the translational inhibition/modification of hypoxiainducible factor-1␣ via impeding JNK signaling pathway. These studies suggest a novel regulatory pathway exists through which CCN5 exerts its anti-invasive function. On the basis of these findings, it is plausible that reactivation of CCN5 in miR-10b-positive invasive/metastatic breast cancers alone or in combination with current therapeutic regimens could provide a unique, alternative strategy to existing breast cancer therapy

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