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

• Published in: Tumor biology Vol. 37; no. 4; pp. 5645 - 5651
• Main Authors: Qu, Mei-Hua, Han, Chunhua, Srivastava, Amit Kumar, Cui, Tiantian, Zou, Ning, Gao, Zhi-Qin, Wang, Qi-En
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.04.2016
• Subjects: Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinogenesis - genetics; Cell Line, Tumor; Endosomal Sorting Complexes Required for Transport - biosynthesis; Endosomal Sorting Complexes Required for Transport - genetics; Epithelial-Mesenchymal Transition - genetics; Female; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Male; MicroRNAs - biosynthesis; MicroRNAs - genetics; Nedd4 Ubiquitin Protein Ligases; Neoplasm Metastasis; Neoplasm Staging; Original Article; Smad2 Protein - biosynthesis; Transforming Growth Factor beta - genetics; Ubiquitin-Protein Ligases - biosynthesis; Ubiquitin-Protein Ligases - genetics; NEDD4L; miR-93; EMT; Lung cancer; TGF-β signaling
• ISSN: 1010-4283; 1423-0380; 1423-0380
• DOI: 10.1007/s13277-015-4328-8

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.