title: Suppression by heat shock protein 20 of hepatocellular carcinoma cell proliferation via inhibition of the mitogen-activated protein kinases and AKT pathways.
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.
authors.affiliation: Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Matsushima-Nishiwaki
authors.forename: Seiji
authors.initials: S
authors.lastname: Adachi
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshioka
authors.forename: Eisuke
authors.initials: E
authors.lastname: Yasuda
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Yamagishi
authors.forename: Junya
authors.initials: J
authors.lastname: Matsuura
authors.forename: Masato
authors.initials: M
authors.lastname: Muko
authors.forename: Rutsu
authors.initials: R
authors.lastname: Iwamura
authors.forename: Takahiro
authors.initials: T
authors.lastname: Noda
authors.forename: Hidenori
authors.initials: H
authors.lastname: Toyoda
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kaneoka
authors.forename: Yukio
authors.initials: Y
authors.lastname: Okano
authors.forename: Takashi
authors.initials: T
authors.lastname: Kumada
authors.forename: Osamu
authors.initials: O
authors.lastname: Kozawa
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation; D050886:HSP20 Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D050886:HSP20 Heat-Shock Proteins; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases