title: NF-κB increased expression of 17β-hydroxysteroid dehydrogenase 4 promotes HepG2 proliferation via inactivating estradiol.
abstract: Hepatocellular carcinoma (HCC) arises in a setting of chronic inflammation induced by inflammatory cytokines, such as nuclear factor-kappaB (NF-κB). HCC is a male-predominant cancer that can be attenuated by estradiol (E2) in vitro and in vivo. Although 17β-hydroxysteroid dehydrogenase 4 (HSD17B4) has been implicated as an estradiol-inactivating enzyme, and its promoter sequence contains two putative NF-κB elements: it is currently unknown whether HSD17B4 is the link between inflammation, estradiol and proliferation in hepatoma cells. In this study, HepG2 cells were used to investigate the role of HSD17B4 in the proliferation of liver cancer cells treated with the NF-κB activator, tumor necrosis factor-alpha (TNF-α), with the inhibitor of NF-κB activation, pyrrolidinedithiocarbamate (PDTC), or with a related specific siRNA. We demonstrated that the human HSD17B4 gene is a target for NF-κB activation in inflammation-stimulated HepG2 cells. HSD17B4 is up-regulated via the binding of activated NF-κB to the distal NF-κB-responsive element via TNF-α stimulation, which then promotes cell proliferation by decreasing the levels of E2 and enhancing the expression of interleukin 6 (IL-6), cyclin D1 and proliferating cell nuclear antigen (PCAN). These results from HepG2 cells are consistent with the observation that HSD17B4 is highly expressed and activated NF-κB is highly co-localized with the NF-κB-responsive element of HSD17B4 in liver tumor tissues from HCC patients. Our findings indicate for the first time that HSD17B4 plays an important role in aggravated HCC progression and provides a novel therapeutic target for HCC.
authors.affiliation: Department of Biochemistry and Molecular Biology, The Key Laboratory of Neurobiology and Vascular Biology, China Administration of Education, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang 050017, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Biochemistry and Molecular Biology, The Key Laboratory of Neurobiology and Vascular Biology, China Administration of Education, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang 050017, China.
authors.forename: Panpan
authors.initials: P
authors.lastname: Ma
authors.affiliation: Department of Biochemistry and Molecular Biology, The Key Laboratory of Neurobiology and Vascular Biology, China Administration of Education, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang 050017, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Biochemistry and Molecular Biology, The Key Laboratory of Neurobiology and Vascular Biology, China Administration of Education, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang 050017, China.
authors.forename: Min
authors.initials: M
authors.lastname: Yao
authors.affiliation: Department of Biochemistry and Molecular Biology, The Key Laboratory of Neurobiology and Vascular Biology, China Administration of Education, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang 050017, China.
authors.forename: Lianguo
authors.initials: L
authors.lastname: Hou
authors.affiliation: Department of Biochemistry and Molecular Biology, The Key Laboratory of Neurobiology and Vascular Biology, China Administration of Education, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang 050017, China.
authors.forename: Pingping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, The Key Laboratory of Neurobiology and Vascular Biology, China Administration of Education, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang 050017, China. Electronic address: jianglingling1959@163.com.
authors.forename: Lingling
authors.initials: L
authors.lastname: Jiang
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D064029:Peroxisomal Multifunctional Protein-2 / Q000235:genetics* / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D013859:Thiocarbamates / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: C530104:CCND1 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D016328:NF-kappa B; D018809:Proliferating Cell Nuclear Antigen; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; C066229:prolinedithiocarbamate; D019938:Cyclin D1; D004958:Estradiol; D011392:Proline; D064029:Peroxisomal Multifunctional Protein-2; C104587:HSD17B4 protein, human
keywords: E2; HCC; HSD17B4; HepG2; NF-κB