Mechanistic study on growth suppression and apoptosis induction by targeting Hepatoma-derived growth factor in human Hepatocellular Carcinoma HepG2 cells

Tsun Yee Tsang, Wan Yee Tang, Wing Pui Tsang, Ngai Na Co, Siu Kai Kong, Tim Tak Kwok

Research output: Contribution to journalArticlepeer-review

Abstract

Hepatoma-derived growth factor (HDGF) is frequently overexpressed in human cancer. The growth factor was previously demonstrated to be a survival factor as knock-down of HDGF suppresses the growth and induces apoptosis in human cancer cells through the Bad-mediated intrinsic apoptotic pathway. However, inactivation of Bad cannot completely repress the apoptosis induced upon HDGF knock-down, indicating the presence of other unidentified pathways. In the present study, HDGF knock-down was shown to trigger the Fas-mediated extrinsic apoptotic pathway in human hepatocellular carcinoma HepG2 cells through NF-κB signaling pathway. Increases in Fas expression and fas promoter activity were detected upon HDGF knock-down by Western blot analysis and luciferase reporter assay. Knock-down of fas inhibited HDGF knock-down effect on apoptosis induction and growth suppression as revealed by annexin V binding assay and soft agar assay. Down-regulation of IκBα was also observed upon HDGF knock-down. Overexpression of IκBα by transient transfection or inhibition of NF-κB by BAY11-7082 suppressed HDGF knock-down effect on fas promoter activation, Fas up-regulation, apoptosis induction and growth suppression. Furthermore, the interaction of Fas-mediated extrinsic and Bad-mediated intrinsic apoptotic pathways was demonstrated as a stronger inhibition on apoptosis induction and growth suppression upon HDGF knock-down was observed when both pathways were inactivated. The results therefore suggested that, through both intrinsic and extrinsic apoptotic pathways, HDGF may function as a survival factor and be a potential target for cancer therapy.

Original languageEnglish (US)
Pages (from-to)253-262
Number of pages10
JournalCellular Physiology and Biochemistry
Volume24
Issue number3-4
DOIs
StatePublished - 2009
Externally publishedYes

Keywords

  • Anchorage-independent growth
  • Apoptosis
  • Bad
  • Fas
  • HDGF
  • NFκB/IκB

ASJC Scopus subject areas

  • Physiology

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