Role of low-molecular-weight heat shock proteins and the molecular mechanism in hepatocellular carcinoma cell proliferation

• Project/Area Number: 22590726
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Gifu University
• Principal Investigator: KOZAWA Osamu 岐阜大学, 大学院・医学系研究科, 教授 (90225417)
• Co-Investigator(Kenkyū-buntansha): ADACHI Seiji 岐阜大学, 大学院・医学系研究科, 非常勤講師 (50467205)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2010: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 肝臓学 / 肝がん細胞 / 低分子量ストレス蛋白質 / 細胞増殖 / 肝細胞がん / ストレス蛋白

Research 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. Our results strongly suggest that HSP20 suppresses the growth of HCC cells via p44/p42mitogen-activated protein kinase and AKT signaling pathways, thus suggesting that the HSP20 could be a new therapeutic target for HCC.

Research Products

• [Journal Article] Significant correlation between the acceleration of platelet aggregation and phosphorylation of HSP27 at Ser-78 in diabetic patients. (2012)
  • Author(s): okuda H, Kato K, Kasahara S, Matsushima-Nishiwaki R, Mizuno T, Sakakibara S and Kozawa O.
  • Journal Title: Int. J. Mol. Med. Volume: 30巻 Issue: 6 Pages: 1387-1395
  • DOI: 10.3892/ijmm.2012.1146
  • Peer Reviewed
• [Journal Article] Cisplatin and ultra-violet-C synergistically down-regulate receptor tyrosine kinases in human colorectal cancer cells. (2012)
  • Author(s): Kawaguchi J, Adachi S, Yasuda I, Yamauchi T, Nakashima M, Ohno T, Shimizu M, Yoshioka T, Itani M, Kozawa O and Moriwaki H.
  • Journal Title: Mol. Cancer. Volume: 11巻 Issue: 1 Pages: 45-45
  • DOI: 10.1186/1476-4598-11-45
  • Peer Reviewed
• [Journal Article] UVC irradiation suppresses platelet-derived growth factor-BB-induced migration in human pancreatic cancer cells. (2012)
  • Author(s): Kawaguchi J, Adachi S, Yasuda I, Yamauchi T, Yoshioka T, Itani M, Kozawa O and Moriwaki H.
  • Journal Title: Oncol. Rep. Volume: 27巻 Issue: 4 Pages: 935-939
  • DOI: 10.3892/or.2011.1612
  • Peer Reviewed
• [Journal Article] Phosphorylation status of heat shock protein 27 plays a key role in gemcitabine-induced apoptosis of pancreatic cancer cells. (2011)
  • Author(s): Nakashima M, Adachi S, Yasuda I, Yamauchi T, Kawaguchi J, Itani M, Yoshioka T, Matsushima-Nishiwaki R, Hirose Y, Kozawa O and Moriwaki H.
  • Journal Title: Cancer Lett. Volume: 313巻 Issue: 2 Pages: 218-225
  • DOI: 10.1016/j.canlet.2011.09.008
  • Peer Reviewed
• [Journal Article] Ultraviolet enhances the sensitivity of pancreatic cancer cells to gemcitabine byactivation of 5' AMP-activated protein kinase. (2011)
  • Author(s): Adachi S, Yasuda I, Kawaguchi J, Yamauchi T, Nakashima M, Itani M, Nakamura M, Yoshioka T, Moriwaki H and Kozawa O.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 414巻 Issue: 1 Pages: 53-59
  • DOI: 10.1016/j.bbrc.2011.09.020
  • Peer Reviewed
• [Journal Article] Suppression by heat shock protein 20 of hepatocellular carcinoma cell proliferation via inhibition of the mitogen-activated protein kinases and Akt pathways. (2011)
  • Author(s): Matsushima-Nishiwaki R, Adachi S,Yoshioka T, Yasuda E, Yamagishi Y, Matsuura J, Muko M, Iwamura R, NodaT, Toyoda H, Kaneoka Y, Okano Y, Kumada T and Kozawa O.
  • Journal Title: J. Cell. Biochem. Volume: 112巻 Issue: 11 Pages: 3430-3439
  • DOI: 10.1002/jcb.23270
  • Peer Reviewed
• [Journal Article] Role of HSP27 in tumor necrosis factor-α-stimulated interleukin-6 synthesis in osteoblasts. (2011)
  • Author(s): Kato K, Tokuda H, Mizutani J, Adachi S, Matsushima-Nishiwaki R, Natsume H, Kozawa O and Otsuka T .
  • Journal Title: Int. J. Mol. Med. Volume: 28巻 Pages: 887-893
  • DOI: 10.3892/ijmm.2011.762
  • NAID: 120006341975
  • Peer Reviewed
• [Journal Article] Ultra-violet irradiation induces apoptosis via mitochondrial pathway in pancreatic cancer cells. (2011)
  • Author(s): Yamauchi T, Adachi S, Yasuda I, Nakashima M, Kawaguchi J, Yoshioka T,Hirose Y, Kozawa O and Moriwaki H.
  • Journal Title: Int. J. Oncol. Volume: 39巻 Pages: 1375-1380
  • DOI: 10.3892/ijo.2011.1188
  • NAID: 120006341977
  • Peer Reviewed
• [Journal Article] Ultraviolet irradiation can induce evasion of colon cancer cells from stimulation of epidermal growth factor. (2011)
  • Author(s): Adachi S, Yasuda I, Nakashima M, Yamauchi T, Kawaguchi J, Shimizu M, Itani M, Nakamura M, Nishii Y, Yoshioka T, Hirose Y, Okano Y, Moriwaki H and Kozawa O.
  • Journal Title: J. Biol. Chem. Volume: 286巻 Issue: 29 Pages: 26178-26187
  • DOI: 10.1074/jbc.m111.240630
  • Peer Reviewed
• [Journal Article] Inhibition of Rho-associated coiled-coil containing protein kinase enhances the activation of epidermal growth factor receptor in pancreatic cancer cells. (2011)
  • Author(s): Nakashima M, Adachi S, Yasuda I, Yamauchi T, Kawaguchi J, Hanamatsu T,Yoshioka T , Okano Y, Hirose Y, Kozawa O and Moriwaki H.
  • Journal Title: Mol. Cancer. Volume: 10巻 Pages: 79-79
  • NAID: 120006341951
  • Peer Reviewed
• [Journal Article] UV-C irradiation induces downregulationof EGF receptors via phosphorylation at serine 1046/1047 in human pancreatic cancer cells. (2011)
  • Author(s): Yamauchi T, Adachi S, Yasuda I, Nakashima M, Kawaguchi J, Nishii Y, Yoshioka T, Okano Y, Hirose Y, Kozawa O and Moriwaki H.
  • Journal Title: Radiat. Res. Volume: 176巻 Pages: 565-574
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/21692654
  • Peer Reviewed
• [Journal Article] Regulation by heat shock protein 27 ofosteocalcin synthesis in osteoblasts. (2011)
  • Author(s): Kato K, Adachi S, Matsushima-Nishiwaki R, Minamitani C,Natsume H, Katagiri Y, Hirose Y, Mizutani J, Tokuda H, Kozawa O and Otsuka T.
  • Journal Title: Endocrinology. Volume: 152巻 Issue: 5 Pages: 1872-1882
  • DOI: 10.1210/en.2010-1062
  • Peer Reviewed
• [Journal Article] cAMP regulates ADP-induced HSP27 phosphorylation in human platelets. (2011)
  • Author(s): Enomoto Y, Adachi S, Doi T, Natsume H, Kato K, Matsushima-Nishiwaki R, Akamatsu S, Tokuda H, Yoshimura S, Otsuka T, Ogura S, Kozawa O and Iwama T .
  • Journal Title: Int. J. Mol. Med. Volume: 27巻 Issue: 5 Pages: 695-700
  • DOI: 10.3892/ijmm.2011.637
  • NAID: 120006341953
  • Peer Reviewed
• [Journal Article] Role of heat shock protein 27 in transforming growth factor-β-stimulatedvascular endothelial growth factor release in osteoblasts. (2011)
  • Author(s): Kato K, Tokuda H, Adachi S, Matsushima-Nishiwaki R, Yamauchi J, Natsume H, Minamitani C, Mizutani J,Otsuka T and Kozawa O.
  • Journal Title: Int. J. Mol. Med. Volume: 27巻 Issue: 3 Pages: 423-428
  • DOI: 10.3892/ijmm.2011.595
  • Peer Reviewed
• [Journal Article] Rho-kinase inhibitor upregulates migration by altering focal adhesion formation via the Akt pathway in colon cancer cells. (2011)
  • Author(s): Adachi S, Yasuda I, Nakashima M, Yamauchi T, Yoshioka T, Okano Y, Moriwaki H and Kozawa O.
  • Journal Title: Eur. J. Pharmacol. Volume: 650巻 Issue: 1 Pages: 145-150
  • DOI: 10.1016/j.ejphar.2010.10.014
  • Peer Reviewed
• [Journal Article] Phosphorylation status of heat shock protein 27 regulates the interleukin-1β-induced interleukin-6 synthesis in C6 glioma cells. (2010)
  • Author(s): Tanabe K, Matsushima-Nishiwaki R,Dohi S and Kozawa O.
  • Journal Title: Neuroscience. Volume: 170巻 Issue: 4 Pages: 1028-1034
  • DOI: 10.1016/j.neuroscience.2010.08.014
  • Peer Reviewed
• [Journal Article] Antithrombin III reduces collagen-stimulated granule secretion of PDGF-AB and the release of soluble CD40 ligand from human platelets. (2010)
  • Author(s): Doi T, Adachi S, Matsushima-Nishiwaki R, Kato H, Enomoto Y, Natsume H, Kato K, Mizutani J, Otsuka T, Tokuda H, Akamatsu S, Iwama T, Kozawa O and Ogura S.
  • Journal Title: Int. J. Mol. Med. Volume: 26巻 Pages: 387-392
  • NAID: 120006341935
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/20664955
  • Peer Reviewed
• [Journal Article] Rho-kinase regulates prostaglandin D2-stimulated heat shock protein 27 induction in osteoblasts. (2010)
  • Author(s): Kato K, Tokuda H, Natsume H, Adachi S, Matsushima-Nishiwaki R, Minamitani C, Mizutani J, Kozawa O and Otsuka T.
  • Journal Title: Exp. Ther. Med. Volume: 1巻 Pages: 579-583
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/22993579
  • Peer Reviewed
• [Journal Article] HSP90 inhibitors induce down-regulation of EGF receptor via p38 MAPK-mediated phosphorylation at Ser1046/7 in human pancreatic cancer cells. (2010)
  • Author(s): Adachi S, Yasuda I, Natsume H, Nakashima M, Moriwaki H and Kozawa O.
  • Journal Title: Oncol. Rep. Volume: 23巻 Pages: 1709-1714
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/?term=kozawa+HSP90+2010
  • Peer Reviewed
• [Journal Article] Evaluation for clinicalutility of glypican-3 (GPC3), measured by a commercially available ELISA kit with GPC3 antibody,as aserological andhistological marker forhepatocellular carcinoma. (2010)
  • Author(s): Yasuda E, Kumada T, Toyoda H, Kaneoka Y, Maeda A, Okuda S, YoshimiN and Kozawa O.
  • Journal Title: Hepatol. Res. Volume: 40巻 Issue: 5 Pages: 477-485
  • DOI: 10.1111/j.1872-034x.2010.00624.x
  • Peer Reviewed
• [Journal Article] Mechanism of collagen-induced release of 5-HT, PDGF-AB and sCD40L from human platelets: role of HSP27 phosphorylation via p44/p42 MAPK. (2010)
  • Author(s): Kato H, Adachi S, Doi T, Matsushima-Nishiwaki R, Minamitani C,Akamatsu S, Enomoto Y, Tokuda H,OtsukaT, Iwama T, Kozawa O and Ogura S.
  • Journal Title: Thromb. Res. Volume: 12巻 Issue: 1 Pages: 39-43
  • DOI: 10.1016/j.thromres.2009.12.003
  • Peer Reviewed
• [Presentation] 肝がんとストレス蛋白質(HSP:HeatShockProtein):特に低分子量 HSP との関連において (2013)
  • Author(s): 小澤 修
  • Organizer: 第7回日本肝がん分子標的治療研究会 教育講演
  • Place of Presentation: 岐阜
  • Year and Date: 2013-01-19
• [Presentation] 肝がんとｽﾄﾚｽ蛋白質（HSP:Heat Shock Protein):特に低分子量HSPとの関連において (2013)
  • Author(s): 小澤 修
  • Organizer: 第7回日本肝がん分子標的治療研究会
  • Place of Presentation: 岐阜県岐阜市じゅうろくプラザ
  • Invited
• [Presentation] 骨代謝とストレス蛋白質 (HSP) :特に骨芽細胞における低分子量 HSP27 において (2012)
  • Author(s): 小澤 修
  • Organizer: 第27回日本整形外科学会基礎学術集会 ランチョンセミナー
  • Place of Presentation: 名古屋
  • Year and Date: 2012-10-27
• [Presentation] ゲムシタビン作用機序における HSP27 リン酸化の役割 (2012)
  • Author(s): 中島賢憲、足立政治、安田一朗、河口順二、山内貴裕、森脇久隆、小澤 修
  • Organizer: 第98回 日本消化器病学会総会
  • Place of Presentation: 東京
  • Year and Date: 2012-04-21
• [Presentation] 骨芽細胞における HSP27 によるオステオカルシン産生制御 (2011)
  • Author(s): 加藤賢治、南谷千帆、夏目英雄、 近藤 章、水谷 潤、小澤 修、大塚隆信
  • Organizer: 第26回日本整形外科学会基礎学術集会
  • Place of Presentation: 前橋
  • Year and Date: 2011-10-20
• [Presentation] Heat shock protein 90 阻害剤の膵がん治療への応用 (2010)
  • Author(s): 足立政治、安田一朗、中島賢憲、山内貴裕、森脇久隆、小澤 修
  • Organizer: 第52回 日本消化器病学会大会
  • Place of Presentation: 横浜
  • Year and Date: 2010-10-15
• [Presentation] 骨芽細胞における transforming growth factor-β(TGF-β)による heat shock protein 27 (HSP27)誘導に対する Rho-kinase の役割 (2010)
  • Author(s): 南谷千帆、小澤 修、徳田治彦、夏目英雄、加藤賢治、水谷 潤、福岡宗良、大塚隆信
  • Organizer: 第25回 日本整形外科学会基礎学術集会
  • Place of Presentation: 京都
  • Year and Date: 2010-10-14
• [Presentation] Heat shock protein 90 inhibitors as a possible new candidate for the treatment of human pancreatic cancer (2010)
  • Author(s): Seiji Adachi, Ichiro Yasuda, Masanori Nakashima, Takahiro Yamauchi, Hisataka Moriwaki and Osamu Kozawa.
  • Organizer: 2010 国際膵臓学会
  • Place of Presentation: 福岡
  • Year and Date: 2010-07-11
• [Remarks]
  • URL: http://www.med.gifu-u.ac.jp/pharma/index.htm
• [Remarks] 岐阜大学大学院医学系研究科 分子・構造学講座 薬理病態学講座
  • URL: http://www.med.gifu-u.ac.jp/pharma/index.htm
• [Remarks]
  • URL: http://www.med.gifu-u.ac.jp/pharma/index.htm
• [Remarks]
  • URL: http://www.med.gifu-u.ac.jp/pharma/index.htm