An epigenetic auto-feedback loop regulates TGF-β type II receptor expression and function in NSCLC
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Shanzhong Yang1,2,*, Yong-Jig Cho3,*, Lin Jin1,2, Guandou Yuan1, Arunima Datta1, Phillip Buckhaults1, Pran K. Datta1,2
1Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
2Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA
3Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA
*These authors have contributed equally to this work
Pran K. Datta, e-mail: [email protected]
Keywords: c-Myc, miR-20a, TGF-β, TGF-β type II receptor, miR-145
Received: April 08, 2015 Accepted: July 31, 2015 Published: August 12, 2015
The downregulation of transforming growth factor-β (TGF-β) type II receptor (TβRII) expression and function plays a pivotal role in the loss of the TGF-β-induced tumor suppressor function that contributes to lung cancer progression. The aberrant expression of miRNAs has been shown to be involved in the regulation of oncogenes and tumor suppressor genes. Our current study involving miRNA microarray, northern blot and QRT-PCR analysis shows an inverse correlation between miR-20a and TβRII expression in non-small cell lung cancer (NSCLC) tissues and cell lines. Stable expression of miR-20a downregulates TβRII in lung epithelial cells which results in an inhibition of TGF-β signaling and attenuation of TGF-β-induced cell growth suppression and apoptosis. Stable knock down of miR-20a increases TβRII expression and inhibits tumorigenicity of lung cancer cells in vivo. Oncogene c-Myc promotes miR-20a expression by activating its promoter leading to downregulation of TβRII expression and TGF-ß signaling. MiR-145, which is upregulated by TGF-β, inhibits miR-20a expression by targeting c-Myc and upregulates TβRII expression. These correlations among miRNAs and cellular proteins are supported by TCGA public database using NSCLC specimens. These results suggest a novel mechanism for the loss of TβRII expression and TGF-β-induced tumor suppressor functions in lung cancer through a complex auto-feedback loop TGF-β/miR-145/c-Myc/miR-20a/TβRII.
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