A novel small-form NEDD4 regulates cell invasiveness and apoptosis to promote tumor metastasis

Chia Jung Liao, Hsiang Cheng Chi, Chung Ying Tsai, Dz Chi Chen, Sheng Ming Wu, Yi Hsin Tseng, Yang Hsiang Lin, I. Hsiao Chung, Ching Ying Chen, Syuan Ling Lin, Shiu Feng Huang, Ya Hui Huang, Kwang Huei Lin

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)9341-9354
Number of pages14
Issue number11
Publication statusPublished - 2015
Externally publishedYes


  • Apoptosis
  • Hepatoma
  • Metastasis
  • Prognosis
  • SNEDD4

ASJC Scopus subject areas

  • Oncology


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