title: Heat shock factor 1 accelerates hepatocellular carcinoma development by activating nuclear factor-κB/mitogen-activated protein kinase.
abstract: Heat shock factor 1 (HSF1), a major transactivator of stress responses, has been implicated in carcinogenesis in various organs. However, little is known about the biological functions of HSF1 in the development of hepatocellular carcinoma (HCC). To clarify the functional role of HSF1 in HCC, we established HSF1-knockdown (HSF1 KD) KYN2 HCC cells by stably expressing either small hairpin RNA (shRNA) against HSF1 (i.e. HSF1 KD) or control shRNA (HSF1 control). Tumorigenicity was significantly reduced in orthotopic mice with HSF1 KD cells compared with those with HSF1 control cells. Reduced tumorigenesis in HSF1 KD cells appeared attributable to increased apoptosis and decreased proliferation. Tumor necrosis factor-α-induced apoptosis was increased in HSF1 KD cells and HSF1(-/-) mouse hepatocytes compared with controls. Decreased expression of IκB kinase γ, a positive regulator of nuclear factor-κB, was also observed in HSF1 KD cells and HSF1(-/-) mouse hepatocytes. Furthermore, expression of bcl-2-associated athanogene domain 3 (BAG3) was dramatically reduced in HSF1 KD cells and HSF1(-/-) mouse hepatocytes. We also found that epidermal growth factor-stimulated mitogen-activated protein kinase signaling was impaired in HSF1 KD cells. Clinicopathological analysis demonstrated frequent overexpression of HSF1 in human HCCs. Significant correlations between HSF1 and BAG3 protein levels and prognosis were also observed. In summary, these results identify a mechanistic link between HSF1 and liver tumorigenesis and may provide as a potential molecular target for the development of anti-HCC therapies.
authors.affiliation: Department of Gastroenterology and Hepatology, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Chuma
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakamoto
authors.forename: Akira
authors.initials: A
authors.lastname: Nakai
authors.forename: Shuhei
authors.initials: S
authors.lastname: Hige
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Nakanishi
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Natsuizaka
authors.forename: Goki
authors.initials: G
authors.lastname: Suda
authors.forename: Takuya
authors.initials: T
authors.lastname: Sho
authors.forename: Kanako
authors.initials: K
authors.lastname: Hatanaka
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsuno
authors.forename: Hideki
authors.initials: H
authors.lastname: Yokoo
authors.forename: Toshiya
authors.initials: T
authors.lastname: Kamiyama
authors.forename: Akinobu
authors.initials: A
authors.lastname: Taketomi
authors.forename: Gen
authors.initials: G
authors.lastname: Fujii
authors.forename: Kosuke
authors.initials: K
authors.lastname: Tashiro
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hikiba
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Asaka
authors.forename: Shin
authors.initials: S
authors.lastname: Maeda
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000076249:Heat Shock Transcription Factors; D022781:Hepatocytes; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D016328:NF-kappa B; D034741:RNA, Small Interfering; D014157:Transcription Factors; D020928:Mitogen-Activated Protein Kinases