Epidermal growth factor induces tumour marker AKR1B10 expression through activator protein-1 signalling in hepatocellular carcinoma cells.

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  • Additional Information
    • Source:
      Publisher: Published by Portland Press on behalf of the Biochemical Society Country of Publication: England NLM ID: 2984726R Publication Model: Print Cited Medium: Internet ISSN: 1470-8728 (Electronic) Linking ISSN: 02646021 NLM ISO Abbreviation: Biochem J Subsets: MEDLINE
    • Publication Information:
      Original Publication: London, UK : Published by Portland Press on behalf of the Biochemical Society
    • Subject Terms:
      Aldehyde Reductase/*metabolism ; Carcinoma, Hepatocellular/*metabolism ; Epidermal Growth Factor/*pharmacology ; Liver Neoplasms/*metabolism ; Transcription Factor AP-1/*metabolism; Aldehyde Reductase/genetics ; Aldo-Keto Reductases ; Animals ; Base Sequence ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/pathology ; DNA Primers/genetics ; Female ; Genes, fos ; Hep G2 Cells ; Humans ; Insulin/pharmacology ; Liver Neoplasms/genetics ; Liver Neoplasms/pathology ; Mice ; Mice, Nude ; Promoter Regions, Genetic ; RNA, Small Interfering/genetics ; Signal Transduction/drug effects ; Transcription Factor AP-1/antagonists & inhibitors ; Transcription Factor AP-1/genetics ; Up-Regulation/drug effects
    • Abstract:
      AKR1B10 (aldo-keto reductase 1B10) is overexpressed in liver and lung cancer, and plays a critical role in tumour development and progression through promoting lipogenesis and eliminating cytotoxic carbonyls. AKR1B10 is a secretory protein and potential tumour marker; however, little is known about the regulatory mechanism of AKR1B10 expression. The present study showed that AKR1B10 is induced by mitogen EGF (epidermal growth factor) and insulin through the AP-1 (activator protein-1) signalling pathway. In human HCC (hepatocellular carcinoma) cells (HepG2 and Hep3B), EGF (50 ng/ml) and insulin (10 nM) stimulated endogenous AKR1B10 expression and promoter activity. In the AKR1B10 promoter, a putative AP-1 element was found at bp -222 to -212. Deletion or mutation of this AP-1 element abrogated the basal promoter activity and response to EGF and AP-1 proteins. This AP-1 element bound to nuclear proteins extracted from HepG2 cells, and this binding was stimulated by EGF and insulin in a dose-dependent manner. Chromatin immunoprecipitation showed that the AP-1 proteins c-Fos and c-Jun were the predominant factors bound to the AP-1 consensus sequence, followed by JunD and then JunB. The same order was followed in the stimulation of endogenous AKR1B10 expression by AP-1 proteins. Furthermore, c-Fos shRNA (short hairpin RNA) and AP-1 inhibitors/antagonists (U0126 and Tanshinone IIA) inhibited endogenous AKR1B10 expression and promoter activity in HepG2 cells cultured in vitro or inoculated subcutaneously in nude mice. U0126 also inhibited AKR1B10 expression induced by EGF. Taken together, these results suggest that AKR1B10 is up-regulated by EGF and insulin through AP-1 mitogenic signalling and may be implicated in hepatocarcinogenesis.
    • Grant Information:
      R21 CA122327 United States CA NCI NIH HHS; CA122327 United States CA NCI NIH HHS
    • Accession Number:
      0 (Biomarkers, Tumor)
      0 (DNA Primers)
      0 (Insulin)
      0 (RNA, Small Interfering)
      0 (Transcription Factor AP-1)
      62229-50-9 (Epidermal Growth Factor)
      EC 1.1.1.- (AKR1B10 protein, human)
      EC 1.1.1.- (Aldo-Keto Reductases)
      EC 1.1.1.21 (Aldehyde Reductase)
    • Publication Date:
      Date Created: 20120215 Date Completed: 20120409 Latest Revision: 20211021
    • Publication Date:
      20221213
    • Accession Number:
      10.1042/BJ20111322
    • Accession Number:
      22329800