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

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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 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.

Original languageEnglish
Article numberbgt343
Pages (from-to)272-281
Number of pages10
JournalCarcinogenesis
Volume35
Issue number2
DOIs
Publication statusPublished - Feb 1 2014

All Science Journal Classification (ASJC) codes

  • Cancer Research

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    Chuma, M., Sakamoto, N., Nakai, A., Hige, S., Nakanishi, M., Natsuizaka, M., Suda, G., Sho, T., Hatanaka, K., Matsuno, Y., Yokoo, H., Kamiyama, T., Taketomi, A., Fujii, G., Tashiro, K., Hikiba, Y., Fujimoto, M., Asaka, M., & Maeda, S. (2014). Heat shock factor 1 accelerates hepatocellular carcinoma development by activating nuclear factor-κB/mitogen-activated protein kinase. Carcinogenesis, 35(2), 272-281. [bgt343]. https://doi.org/10.1093/carcin/bgt343