title: Phosphorylated Heat Shock Protein 20 (HSPB6) Regulates Transforming Growth Factor-α-Induced Migration and Invasion of Hepatocellular Carcinoma Cells.
abstract: Human hepatocellular carcinoma (HCC) is one of the major malignancies in the world. Small heat shock proteins (HSPs) are reported to play an important role in the regulation of a variety of cancer cell functions, and the functions of small HSPs are regulated by post-translational modifications such as phosphorylation. We previously reported that protein levels of a small HSP, HSP20 (HSPB6), decrease in vascular invasion positive HCC compared with those in the negative vascular invasion. Therefore, in the present study, we investigated whether HSP20 is implicated in HCC cell migration and the invasion using human HCC-derived HuH7 cells. The transforming growth factor (TGF)-α-induced migration and invasion were suppressed in the wild-type-HSP20 overexpressed cells in which phosphorylated HSP20 was detected. Phospho-mimic-HSP20 overexpression reduced the migration and invasion compared with unphosphorylated HSP20 overexpression. Dibutyryl cAMP, which enhanced the phosphorylation of wild-type-HSP20, significantly reduced the TGF-α-induced cell migration of wild-type HSP20 overexpressed cells. The TGF-α-induced cell migration was inhibited by SP600125, a c-Jun N-terminal kinases (JNK) inhibitor. In phospho-mimic-HSP20 overexpressed HuH7 cells, TGF-α-stimulated JNK phosphorylation was suppressed compared with the unphosphorylated HSP20 overexpressed cells. Moreover, the level of phospho-HSP20 protein in human HCC tissues was significantly correlated with tumor invasion. Taken together, our findings strongly suggest that phosphorylated HSP20 inhibits TGF-α-induced HCC cell migration and invasion via suppression of the JNK signaling pathway.
authors.affiliation: Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Matsushima-Nishiwaki
authors.affiliation: Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Gifu, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Toyoda
authors.affiliation: Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Nagasawa
authors.affiliation: Department of Radiological Technology, Suzuka University of Medical Science, Suzuka, Mie, Japan.
authors.forename: Eisuke
authors.initials: E
authors.lastname: Yasuda
authors.affiliation: Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Naokazu
authors.initials: N
authors.lastname: Chiba
authors.affiliation: Department of Medical Technology, Ogaki Municipal Hospital, Ogaki, Gifu, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Okuda
authors.affiliation: Department of Surgery, Ogaki Municipal Hospital, Ogaki, Gifu, Japan.
authors.forename: Atsuyuki
authors.initials: A
authors.lastname: Maeda
authors.affiliation: Department of Surgery, Ogaki Municipal Hospital, Ogaki, Gifu, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kaneoka
authors.affiliation: Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Gifu, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kumada
authors.affiliation: Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Kozawa
mesh_terms: D000873:Anthracenes / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D055551:HSP27 Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000873:Anthracenes; D055551:HSP27 Heat-Shock Proteins; C550985:HSPB7 protein, human; D009363:Neoplasm Proteins; D016211:Transforming Growth Factor alpha; C432165:pyrazolanthrone; D048670:MAP Kinase Kinase 4