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miR-93 promotes TGF-β-induced epithelial-to-mesenchymal transition through downregulation of NEDD4L in lung cancer cells

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Tumor Biology

Abstract

The level of microRNA-93 (miR-93) in tumors has been recently reported to be negatively correlated with survival of lung cancer patients. Considering that the most devastating aspect of lung cancer is metastasis, which can be promoted by transforming growth factor-β (TGF-β)-induced epithelial-to-mesenchymal transition (EMT), we sought to determine whether miR-93 is involved in this process. Here, we report that a previously unidentified target of miR-93, neural precursor cell expressed developmentally downregulated gene 4-like (NEDD4L), is able to mediate TGF-β-mediated EMT in lung cancer cells. miR-93 binds directly to the 3′-UTR of the NEDD4L messenger RNA (mRNA), leading to a downregulation of NEDD4L expression at the protein level. We next demonstrated that the downregulation of NEDD4L enhanced, while overexpression of NEDD4L reduced TGF-β signaling, reflected by increased phosphorylation of SMAD2 in the lung cancer cell line after TGF-β treatment. Furthermore, overexpression of miR-93 in lung cancer cells promoted TGF-β-induced EMT through downregulation of NEDD4L. The analysis of publicly available gene expression array datasets indicates that low NEDD4L expression correlates with poor outcomes among patients with lung cancer, further supporting the oncogenic role of miR-93 in lung tumorigenesis and metastasis.

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Acknowledgments

This work was supported by the National Institute of Health (CA151248 to Q.E.W.). This research also received grant support from Shandong Provincial Education Association for International Exchanges (M. H. Q.) and the Shandong Provincial Natural Science Foundation, China, ZR2011HM043 (Z. G.).

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Authors and Affiliations

  1. Department of Pharmacology, Key Lab of Applied Pharmacology in Universities of Shandong, Weifang Medical University, 7166 Baotong West St, Weifang, 261053, Shandong, China

    Mei-Hua Qu & Zhi-Qin Gao

  2. Department of Radiology, The Ohio State University Wexner Medical Center, Room 1014, 460 W. 12th Ave, Columbus, OH, 43210, USA

    Mei-Hua Qu, Chunhua Han, Amit Kumar Srivastava, Tiantian Cui, Ning Zou & Qi-En Wang

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  1. Mei-Hua Qu
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  2. Chunhua Han
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  4. Tiantian Cui
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Correspondence to Mei-Hua Qu or Qi-En Wang.

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Qu, MH., Han, C., Srivastava, A.K. et al. miR-93 promotes TGF-β-induced epithelial-to-mesenchymal transition through downregulation of NEDD4L in lung cancer cells. Tumor Biol. 37, 5645–5651 (2016). https://doi.org/10.1007/s13277-015-4328-8

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  • DOI: https://doi.org/10.1007/s13277-015-4328-8

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