A novel small-form NEDD4 regulates cell invasiveness and apoptosis to promote tumor metastasis
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Chia-Jung Liao1, Hsiang-Cheng Chi1, Chung-Ying Tsai1, Chi-De Chen2, Sheng-Ming Wu1, Yi-Hsin Tseng1, Yang-Hsiang Lin1, I-Hsiao Chung1, Ching-Ying Chen1, Syuan-Ling Lin1, Shiu-Feng Huang3, Ya-Hui Huang4, Kwang-Huei Lin1
1Department of Biochemistry, Chang-Gung University, Taoyuan, Taiwan 333, Republic of China
2Chang Gung Molecular Medicine Research Center, Chang-Gung University, Taoyuan, Taiwan 333, Republic of China
3Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan 350, Republic of China
4Medical Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan 333, Republic of China
Kwang-Huei Lin, e-mail: firstname.lastname@example.org
Keywords: Hepatoma, prognosis, sNEDD4, metastasis, apoptosis
Received: October 21, 2014 Accepted: February 09, 2015 Published: March 20, 2015
Despite numerous investigations on metastasis, the determinants of metastatic processes remain unclear. We aimed to identify the metastasis-associated genes in hepatocellular carcinoma (HCC). Potent metastatic SK-hep-1 (SK) cells, designated ‘SKM’, were generated using Transwell assay followed by selection in a mouse model. Genes expressed differentially in SKM and SK cells were identified via microarray analyses. A small form of Neural precursor cell-expressed developmentally downregulated 4 (sNEDD4) was identified to be overexpressed in SKM cells, which was confirmed as a novel transcript using liquid chromatography-mass spectrometry. In clinical specimens, sNEDD4 was significantly overexpressed in tumors and serves as a poor prognostic factor for male patients with HCC (P = 0.035). Upon subcutaneous introduction of sNEDD4-overexpressing SK cells into flanks of nude mice, tumors grew faster than those of the control group. Furthermore, sNEDD4-mediated promotion of tumor metastasis was demonstrated in the orthotopic mouse model. Overexpression of sNEDD4 increased the invasive ability of SK cells through upregulation of matrix metalloproteinase 9 and inhibited serum deprivation-induced apoptosis via upregulation of myeloid cell leukemia 1. In conclusion, sNEDD4 is a novel metastasis-associated gene, which prevents apoptosis under nutrient restriction conditions. The present findings clearly support the prognostic potential of sNEDD4 for HCC.
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