Suppression by heat shock protein 20 of hepatocellular carcinoma cell proliferation via inhibition of the mitogen‐activated protein kinases and AKT pathways |
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Authors: | Rie Matsushima‐Nishiwaki Seiji Adachi Takashi Yoshioka Eisuke Yasuda Yasumasa Yamagishi Junya Matsuura Masato Muko Rutsu Iwamura Takahiro Noda Hidenori Toyoda Yuji Kaneoka Yukio Okano Takashi Kumada Osamu Kozawa |
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Institution: | 1. Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501‐1194, Japan;2. Department of Molecular Pathobiochemistry, Gifu University Graduate School of Medicine, Gifu 501‐1194, Japan;3. Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Gifu 503‐8502, Japan;4. Department of Surgery, Ogaki Municipal Hospital, Ogaki, Gifu 503‐8502, Japan |
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Abstract: | Heat shock protein (HSP) 20, one of the low‐molecular weight HSPs, is known to have versatile functions, such as vasorelaxation. However, its precise role in cancer proliferation remains to be elucidated. While HSP20 is constitutively expressed in various tissues including the liver, we have previously reported that HSP20 protein levels in human hepatocellular carcinoma (HCC) cells inversely correlate with the progression of HCC. In this study, we investigated the role of HSP20 in HCC proliferation. The activities of extracellular signal‐regulated kinase (ERK), c‐jun N‐terminal kinase (JNK), and AKT were negatively correlated with the HSP20 protein levels in human HCC tissues. Since HSP20 proteins were hardly detected in HCC‐derived cell lines, the effects of HSP20 expression were evaluated using human HCC‐derived HuH7 cells that were stably transfected with wild‐type human HSP20 (HSP20 overexpressing cells). In HSP20 overexpressing cells, cell proliferation was retarded, and the activation of the mitogen‐activated protein kinases (MAPKs) signaling pathways, including the ERK and JNK, and AKT pathways, as well as cyclin D1 accumulation induced by either transforming growth factor‐α (TGFα) or hepatocyte growth factor, were significantly suppressed compared with the empty vector‐transfected cells (control cells). Taken together, our findings strongly suggest that HSP20 suppresses the growth of HCC cells via the MAPKs and AKT signaling pathways, thus suggesting that the HSP20 could be a new therapeutic target for HCC. J. Cell. Biochem. 112: 3430–3439, 2011. © 2011 Wiley Periodicals, Inc. |
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Keywords: | HSP20 HEPATOCCELLULAR CARCINOMA GROWTH FACTOR MAPK AKT |
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