Journal Article

Stat3-coordinated Lin-28–let-7–HMGA2 and miR-200–ZEB1 circuits initiate and maintain oncostatin M-driven epithelial–mesenchymal transition

Hu, M, Yu, M, Guo, N, Diao, D, Shi, M, Chen, C, Guo, L, Qian, L, Chen, X, Wang, F

2013

Overview

Inflammation can act as a crucial mediator of epithelial-to-mesenchymal transition (EMT). In this study, we show that oncostatin M (OSM) is expressed in an autocrine/paracrine fashion in invasive breast carcinoma. OSM stimulation promotes spontaneous lung metastasis of MCF-7 xenografts in nude mice. A conspicuous epigenetic transition was induced by OSM stimulation not only in breast cancer cell lines but also in MCF-7 xenografts in nude mice. The expression of miR-200 and let-7 family members in response to OSM stimulation was downregulated in a signal transducer and activator of transcription factor 3 (Stat3)-dependent manner, resulting in comprehensive alterations of the transcription factors and oncoproteins targeted by these microRNAs. Inhibition of Stat3 activation or the ectopic expression of let-7 and miR-200 effectively reversed the mesenchymal phenotype of breast cancer cells. Stat3 promotes the transcription of Lin-28 by directly binding to the Lin-28 promoter, resulting in the repression of let-7 expression and concomitant upregulation of the let-7 target, high-mobility group A protein 2 (HMGA2). Knock down of HMGA2 significantly impairs OSM-driven EMT. Our data indicate that downregulation of let-7 and miR-200 levels initiates and maintains OSM-induced EMT phenotypes, and HMGA2 acts as a master switch of OSM-induced EMT. These findings highlight the importance of Stat3-coordinated Lin-28B–let-7–HMGA2 and miR-200–ZEB1 circuits in the cytokine-mediated phenotypic reprogramming of breast cancer cells.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67/395 / 631/80/84/2176 / 692/699/67/1347 / Animals / Apoptosis / Breast cancer / Breast Neoplasms - metabolism / Cell Biology / Cell Line, Tumor / Cytokines / Down-Regulation / Epithelial-Mesenchymal Transition - genetics / Epithelial-Mesenchymal Transition - physiology / Female / Gene expression / Gene Knockdown Techniques / Genetic aspects / Heterografts / HMGA2 Protein - biosynthesis / HMGA2 Protein - genetics / Homeodomain Proteins / Human Genetics / Humans / Inflammation / Inflammatory diseases / Internal Medicine / Kruppel-Like Transcription Factors / Lung Neoplasms - secondary / Mammary Neoplasms, Animal - metabolism / MCF-7 Cells / Medicine / Medicine & Public Health / Mice / Mice, Inbred BALB C / MicroRNAs - biosynthesis / MicroRNAs - metabolism / Neoplasm Transplantation / Neoplastic processes / Oncology / Oncostatin M - biosynthesis / Oncostatin M - metabolism / original-article / Promoter Regions, Genetic / RNA-Binding Proteins - biosynthesis / RNA-Binding Proteins - genetics / STAT3 Transcription Factor - metabolism / Statins / Testing / Up-Regulation / Zinc Finger E-box-Binding Homeobox 1