A study to explore the mechanism of hepatic metastasis of colon cancer through Heregulin

• Project/Area Number: 23590423
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Akita University
• Principal Investigator: YOSHIOKA Toshiaki 秋田大学, 医学部, 講師 (80302264)
• Co-Investigator(Kenkyū-buntansha): OMORI Yasufumi 秋田大学, 大学院医学系研究科, 教授 (90323138) ; YAMAMOTO Yohei 秋田大学, 大学院医学系研究科, 助教 (70400512) ; ENOMOTO Katsuhiko 秋田大学, 大学院医学系研究科, 教授 (20151988)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2011: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 肝転移 / 大腸癌 / Heregulin / 肝細胞 / 大腸癌肝転移 / 肝細胞傷害 / 分子標的療法 / 肺転移

Research Abstract

We investigated a mechanism why hepatocytes express Heregulin(HRG) in the situation of hepatic metastasis of colorectal cancer. Immunohistochemical(IHC) examination on human specimen of hepatic metastasis revealed that HRG was expressed in hepatocytes at 88.7 %. The expression was evident in hepatocytes which were close to the metastatic tumor but not in those which were contact to the tumor with being injured nor in far region. Dimethylnitrosoamine(DMN) caused significantly increased expression of HRG mRNA in rat hepatocytes from day 1 compared with that of the control. IHC examination revealed that HRG expression in hepatocytes started from day 1 around the area of Glisson's capsule but not in the area of central zone of hepatic lobules where were injured by DMN. Partial hepatectomy also revealed that hepatocytes in the residual liver expressed HRG. These results suggest that HRG expression is appeared in the residual hepatocytes in the stage of injury and regeneration of the liver.

Research Products

• [Journal Article] Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction (2014)
  • Author(s): Chen, M., Zhang, Y., Yu, VC., Chong, YS., Yoshioka, T., Ge, R.
  • Journal Title: Cell Death Differ Volume: 21 Pages: 797-810
• [Journal Article] Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction (2014)
  • Author(s): Chen M, Zhang Y, Yu V C, Chong Y-S , Yoshioka T and Ge R
  • Journal Title: Cell Death Differ. Volume: 21(5) Issue: 5 Pages: 797-810
  • DOI: 10.1038/cdd.2014.3
  • Peer Reviewed
• [Journal Article] β4 integrin signaling induces expansion of prostate tumor progenitors (2013)
  • Author(s): Yoshioka, T., Otero, J., Chen, Y., Kim, YM., Koutcher, JA., Satagopan, J., Reuter, V., Carver, B., de Stanchina, E., Enomoto, K., Greenberg, NM., Scardino, PT., Scher, HI., Sawyers, CL., Giancotti, FG.
  • Journal Title: J. Clin. Invest. Volume: 123 Pages: 682-699
• [Journal Article] Tumor necrosis factor-α promotes bile ductular transdifferentiation of mature rat hepatocytes in vitro (2013)
  • Author(s): Nishikawa, Y., Sone, M., Nagahama, Y., Kumagai, E., Doi, Y., Omori, Y., Yoshioka, T., Tokairin, T., Yoshida, M., Yamamoto, Y., Ito, A., Sugiyama, T., Enomoto, K.
  • Journal Title: J. Cell. Biochem. Volume: 114 Pages: 831-843
  • NAID: 120006522736
• [Journal Article] Recovery of mature hepatocytic phenotype following bile ductular transdifferentiation of rat hepatocytes in vitro (2012)
  • Author(s): Sone M, Nishikawa Y, Nagahama Y, Kumagai E, Doi Y, Omori Y, Yoshioka T, Tokairin T, Yoshida M, Sugiyama T, Enomoto K.
  • Journal Title: Am J Pathol. Volume: 181 Pages: 2094-2104
  • NAID: 120006658774
• [Journal Article] Cytoplasmic accumulation of connexin32 expands cancer stem cell population in human HuH7 hepatoma cells by enhancing its self-renewal (2011)
  • Author(s): Kawasaki Y, Omori Y, Li Q, Nishikawa Y, Yoshioka T, Yoshida M, Ishikawa K and Enomoto K.
  • Journal Title: Int. J. Cancer Volume: 128 Pages: 51-62
• [Presentation] Reactivity with human cancers and anti- tumor effect of novel anti-HER3 rat monoclonal antibodies (2013)
  • Author(s): Okita, K., Ueda, S., Tokiwa, R., Yagi, H., Inoue, M., Yoshioka, T., Masuko, T.
  • Organizer: 第72回日本癌学会学術総会
• [Presentation] 新規抗HER3ラットモノクローナル抗体のヒト癌に対する反応性と抗腫瘍効果 (2013)
  • Author(s): 沖田 鋼季, 上田 詩歩, 常盤 遼, 八木 秀樹, 井上 正宏, 吉岡 年明, 益子 高
  • Organizer: 第72回 日本癌学会学術集会
  • Place of Presentation: 横浜
• [Presentation] Study of expression of heregulin in the human liver metastasis (2012)
  • Author(s): Yoshioka, T., Nishikawa, Y., Yamamoto, Y., Omori, Y., Nanjo, H., Enomoto, K.
  • Organizer: 第71回日本癌学会総会
• [Presentation] ラット傷害肝および部分肝切除における肝細胞でのheregulin発現の検討 (2012)
  • Author(s): 吉岡年明, 西川祐司, 山本洋平, 大森泰文, 南候博, 榎本克彦
  • Organizer: 第101回日本病理学会総会
• [Presentation] ラット傷害肝および部分肝切除における肝細胞でのheregulin発現の検討 (2012)
  • Author(s): 吉岡年明, 西川祐司, 山本洋平, 大森泰文, 南條 博, 榎本克彦
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京
• [Presentation] Study on heregulin expression of the hepatocyts in liver metastasis and liver injury (2011)
  • Author(s): Omori, Y., Kawasaki, Y., Li, Q., Yo shioka, T., Ya mamoto, Y. and Enomoto, K
  • Organizer: 第71回日本癌学会総会
• [Presentation] 肝転移巣周辺部および傷害肝における肝細胞でのheregulin発現の検討 (2011)
  • Author(s): 吉岡年明, 西川祐司, 山本洋平, 大森泰文, 南條博, 榎本克彦
  • Organizer: 第100回 日本病理学会総会
  • Place of Presentation: 横浜
• [Presentation] Study on heregulin expression of the hepatocytes in liver metastasis and in liver injury (2011)
  • Author(s): Toshiaki Yoshioka, Yuji Nishikawa, Yohei Yamamoto, Yasufumi Omori, Hiroshi Nanjo, Katsuhiko Enomoto
  • Organizer: 70th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Nagoya
• [Presentation] 肝転移巣周辺部および傷害肝における肝細胞でのheregulin発現の検討
  • Author(s): 吉岡年明, 西川祐司, 山本洋平, 大森泰文, 南候博, 榎本克彦
  • Organizer: (2011) 第100回日本病理学会総会
• [Book] Beta4 Integrin induces expansion of prostate tumor progenitors (2013)
  • Author(s): Yoshioka T, Otero J and Giaccotti FG
  • Publisher: Beyond the Abstract
• [Book] Cytoplasmic connex in 32 and self-renewal of cancer stem cells : Implication in metastasis. (2012) In "Hepatocellular Carcinoma – Basic Research" (ed) Lau W-Y, pp235-252 (2012)
  • Author(s): Omori, Y., Kawasaki, Y., Li, Q., Yoshioka, T., Yamamoto, Y. and Enomoto, K.
  • Publisher: InTech, Rijeka
• [Remarks]
  • URL: http://WWW.med.akita-u.ac.jp/~byouri1/