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

Abstract

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.

• Authors: L Guo, C Chen, M Shi, F Wang, X Chen, D Diao, M Hu, M Yu, L Qian, N Guo
• Journal: Oncogene (Oncogene) Vol. 32 Issue 45 Pg. 5272-82 (Nov 07 2013) ISSN: 1476-5594 [Electronic] England
• PMID: 23318420 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HMGA2 Protein
• Homeodomain Proteins
• Kruppel-Like Transcription Factors
• Lin-28 protein, mouse
• MicroRNAs
• Mirn200 microRNA, mouse
• RNA-Binding Proteins
• STAT3 Transcription Factor
• Stat3 protein, mouse
• ZEB1 protein, mouse
• Zinc Finger E-box-Binding Homeobox 1
• mirnlet7 microRNA, mouse
• Oncostatin M

Topics

• Animals
• Breast Neoplasms (metabolism)
• Cell Line, Tumor
• Down-Regulation
• Epithelial-Mesenchymal Transition (genetics, physiology)
• Female
• Gene Knockdown Techniques
• HMGA2 Protein (biosynthesis, genetics)
• Heterografts
• Homeodomain Proteins
• Humans
• Inflammation
• Kruppel-Like Transcription Factors
• Lung Neoplasms (secondary)
• MCF-7 Cells
• Mammary Neoplasms, Animal (metabolism)
• Mice
• Mice, Inbred BALB C
• MicroRNAs (biosynthesis, metabolism)
• Neoplasm Transplantation
• Oncostatin M (biosynthesis, metabolism)
• Promoter Regions, Genetic
• RNA-Binding Proteins (biosynthesis, genetics)
• STAT3 Transcription Factor (metabolism)
• Up-Regulation
• Zinc Finger E-box-Binding Homeobox 1