An epigenetic auto-feedback loop regulates TGF-beta type II receptor expression and function in NSCLC

作者：Yang Shanzhong; Cho Yong Jig; Jin Lin; Yuan Guandou; Datta Arunima; Buckhaults Phillip; Datta Pran K^*

来源：Oncotarget, 2015, 6(32): 33237-33252.

DOI：10.18632/oncotarget.4893

• c-Myc
• miR-20a
• TGF-b
• TGF-b type II receptor
• miR-145

The downregulation of transforming growth factor-beta (TGF-beta) type II receptor (T beta RII) expression and function plays a pivotal role in the loss of the TGF-beta-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 T beta RII expression in non-small cell lung cancer (NSCLC) tissues and cell lines. Stable expression of miR-20a downregulates T beta RII in lung epithelial cells which results in an inhibition of TGF-beta signaling and attenuation of TGF-beta-induced cell growth suppression and apoptosis. Stable knock down of miR-20a increases T beta RII 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 T beta RII expression and TGF-beta signaling. MiR-145, which is upregulated by TGF-beta, inhibits miR-20a expression by targeting c-Myc and upregulates T beta RII 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 T beta RII expression and TGF-beta-induced tumor suppressor functions in lung cancer through a complex auto-feedback loop TGF-beta/miR-145/c-Myc/miR-20a/T beta RII.

• 出版日期2015-10-20