title: Epidermal growth factor induces tumour marker AKR1B10 expression through activator protein-1 signalling in hepatocellular carcinoma cells.
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.
authors.affiliation: Department of Medical Microbiology, Immunology & Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, 913 North Rutledge Street, Springfield, IL 62794, U.S.A.
authors.forename: Ziwen
authors.initials: Z
authors.lastname: Liu
authors.forename: Ruilan
authors.initials: R
authors.lastname: Yan
authors.forename: Ahmed
authors.initials: A
authors.lastname: Al-Salman
authors.forename: Yi
authors.initials: Y
authors.lastname: Shen
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Bu
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.forename: Di-Xian
authors.initials: DX
authors.lastname: Luo
authors.forename: Chenfei
authors.initials: C
authors.lastname: Huang
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Jiang
authors.forename: Andrew
authors.initials: A
authors.lastname: Wilber
authors.forename: Yin-Yuan
authors.initials: YY
authors.lastname: Mo
authors.forename: Mei Chris
authors.initials: MC
authors.lastname: Huang
authors.forename: Yupei
authors.initials: Y
authors.lastname: Zhao
authors.forename: Deliang
authors.initials: D
authors.lastname: Cao
mesh_terms: D000449:Aldehyde Reductase / Q000235:genetics / Q000378:metabolism*; D000074408:Aldo-Keto Reductases; D000818:Animals; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017931:DNA Primers / Q000235:genetics; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005260:Female; D016762:Genes, fos; D056945:Hep G2 Cells; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D014408:Biomarkers, Tumor; D017931:DNA Primers; D007328:Insulin; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D004815:Epidermal Growth Factor; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase