Heat shock factor 1 accelerates hepatocellular carcinoma development by activating nuclear factor-κB/mitogen-activated protein kinase

Makoto Chuma, Naoya Sakamoto, Akira Nakai, Shuhei Hige, Mitsuru Nakanishi, Mitsuteru Natsuizaka, Goki Suda, Takuya Sho, Kanako Hatanaka, Yoshihiro Matsuno, Hideki Yokoo, Toshiya Kamiyama, Akinobu Taketomi, Gen Fujii, Kosuke Tashiro, Yoko Hikiba, Mitsuaki Fujimoto, Masahiro Asaka, Shin Maeda

研究成果: Contribution to journalArticle査読

27 被引用数 (Scopus)

抄録

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 mitogenactivated 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.

本文言語英語
論文番号bgt343
ページ(範囲)272-281
ページ数10
ジャーナルCarcinogenesis
35
2
DOI
出版ステータス出版済み - 2 2014

All Science Journal Classification (ASJC) codes

  • 癌研究

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