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J. Biol. Chem., Vol. 283, Issue 27, 18852-18860, July 4, 2008

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Phosphorylated Heat Shock Protein 27 Represses Growth of Hepatocellular Carcinoma via Inhibition of Extracellular Signal-regulated Kinase^*

Rie Matsushima-Nishiwaki, Shinji Takai, Seiji Adachi, Chiho Minamitani, Eisuke Yasuda, Takahiro Noda, Kanefusa Kato^¶, Hidenori Toyoda, Yuji Kaneoka^||, Akihiro Yamaguchi^||, Takashi Kumada, and Osamu Kozawa¹

From the Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, the Departments of Gastroenterology and ^||Surgery, Ogaki Municipal Hospital, Ogaki, Gifu 503-8502, and the ^¶Department of Biochemistry, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi 480-0392, Japan

Heat shock protein 27, one of the low molecular weight stress proteins, is recognized as a molecular chaperone; however, other functions have not yet been well established. Phosphorylated heat shock protein 27 levels inversely correlate with the progression of human hepatocellular carcinoma. This study shows that phosphorylated heat shock protein 27 interferes with cell growth of the hepatocellular carcinoma-derived HuH7 cells in the presence of the proinflammatory cytokine, tumor necrosis factor-, via inhibition of the sustained activation of the extracellular signal-regulated kinase signal pathway. The activities of Raf/extracellular signal-regulated kinase and subsequent activator protein-1 transactivation and the induction levels of cyclin D1 were lower in HuH7 cells transfected with phosphorylated heat shock protein 27 than those with unphosphorylated heat shock protein 27. Moreover, phosphorylated heat shock protein 27 up-regulated the levels of p38 mitogen-activated protein kinase and mitogen-activated protein kinase phosphatase-1, an inhibitory protein of extracellular signal-regulated kinase. These results indicate that phosphorylated heat shock protein 27 might suppress the extracellular signal-regulated kinase activity in the hepatocellular carcinoma cells via two separate pathways in an inflammatory state. The extracellular signal-regulated kinase activity is inversely correlated with phosphorylated heat shock protein 27 at serine 15 and also in human hepatocellular carcinoma tissues in vivo. Because the extracellular signal-regulated kinase signal pathway is a major proliferation signal of hepatocellular carcinoma, activator protein-1 activation is an early event in hepatocarcinogenesis. These findings strongly suggest that the control of the phosphorylated heat shock protein 27 levels could be a new therapeutic strategy especially to counter the recurrence of hepatocellular carcinoma.

Received for publication, February 19, 2008 , and in revised form, May 8, 2008.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan. Tel.: 81-58-230-6214; Fax: 81-58-230-6215; E-mail: okozawa{at}gifu-u.ac.jp.

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