A study to explore the new molecular target therapy about Heregulin associated molecules concerning to liver metastasis of colon cancer

• Project/Area Number: 18K06981
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Akita University
• Principal Investigator: Yoshioka Toshiaki 秋田大学, 医学系研究科, 教授 (80302264)
• Co-Investigator(Kenkyū-buntansha): 南條 博 秋田大学, 医学部附属病院, 准教授 (70250892)
• Project Period (FY): 2018-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 肝転移 / Heregulin / 肝細胞 / 大腸癌 / 大腸がん肝転移 / 分子標的療法

Outline of Final Research Achievements

We investigated an expression and a role of hepatocyte-secreted Heregulin and a new molecular target therapy about Heregulin associated molecules concerning to liver metastasis of colon cancer. Immunohistochemical examination on human specimen of liver metastasis revealed that 88.7 % cases expressed HRG. Dimethylnitrosoamine caused increased expression of mRNA and protein of HRG in rat hepatocytes. HRG mRNA was increased the expression by cytokines treatment and mouse hepatocytes were proliferated by HRG. A new HER3 antibody repressed the proliferation of cancer cells and growth of xenograft .

Academic Significance and Societal Importance of the Research Achievements

大腸癌の肝転移に関わる様々な分子が報告されているが, 大腸癌と転移先の肝臓の主な構成細胞である肝細胞との相互作用という面から転移のメカニズムを解明した報告は少ない. 本研究において, Heregulinはマウスの大腸癌肝転移巣のみならず, ヒトの大腸癌肝転移巣でも高頻度に癌周囲の肝細胞に発現が確認されたことから, ヒトでも同様のメカニズムが起こっていることが示された。HeregulinのレセプターであるHER3に対して新規に作製した抗体が, 大腸癌細胞の増殖を抑制しヌードマウス皮下に移植した大腸癌腫瘍の増大を抑制したことから, 治療に貢献できる可能性があり学術的, 社会的意義は高いと考える.

Research Products

• [Journal Article] pecific Gut Microbial Environment in Lard Diet-Induced Prostate Cancer Development and Progression. (2022)
  • Author(s): Sato H, Narita S, Ishida M, Takahashi Y, Mingguo H, Kashima S, Yamamoto R, Koizumi A, Nara T, Numakura K, Saito M, Yoshioka T, Habuchi T.
  • Journal Title: Int J Mol Sci. Volume: 23 Issue: 4 Pages: 2214-2214
  • DOI: 10.3390/ijms23042214
  • Peer Reviewed / Open Access
• [Journal Article] Antitumor effects of novel mAbs against cationic amino acid transporter 1 (CAT1) on human CRC with amplified CAT1 gene (2021)
  • Author(s): Okita K, Hara Y, Okura H, Hayashi H, Sasaki Y, Masuko S, Kitadai E, Masuko K, Yoshimoto S, Hayashi N, Sugiura R, Endo Y, Okazaki S, Arai S, Yoshioka T, Matsumoto T, Makino Y, Komiyama H, Sakamoto K, Masuko T.
  • Journal Title: Cancer Sci. Volume: 112 Issue: 2 Pages: 563-574
  • DOI: 10.1111/cas.14741
  • Peer Reviewed / Open Access
• [Journal Article] A case of secretory carcinoma of the minor salivary gland in the buccal mucosa (2021)
  • Author(s): Takano H, Fukada M, Hatakeyama S, Konno Y, Yamazaki M, Igarashi H, Nanjo H, Nagao T, Yoshioka T
  • Journal Title: J Oral Maxillo Surg Med Pathol Volume: 33 Issue: 2 Pages: 136-140
  • DOI: 10.1016/j.ajoms.2020.08.009
  • Peer Reviewed / Open Access
• [Journal Article] Novel functional anti-HER3 monoclonal antibodies with potent anti- cancer effects on various human epithelial cancers. (2020)
  • Author(s): Okita K, Okazaki S, Uejima S, Yamada E, Kaminaka H, Kondo M, Ueda S, Tokiwa R, Iwata R, Yamasaki A, Hayashi N, Ogura D, Hirotani K, Yoshioka T, Inoue M, Masuko K, Masuko T
  • Journal Title: Oncotarget Volume: 11 Issue: 1 Pages: 31-45
  • DOI: 10.18632/oncotarget.27414
  • NAID: 120006888520
  • Peer Reviewed / Open Access
• [Journal Article] Increased fatty acyl saturation of phosphatidylinositol phosphates in prostate cancer progression (2019)
  • Author(s): Koizumi Atsushi、Narita Shintaro、Nakanishi Hiroki、Ishikawa Masaki、Eguchi Satoshi、Kimura Hirotaka、Takasuga Shunsuke、Huang Mingguo、Inoue Takamitsu、Sasaki Junko、Yoshioka Toshiaki、Habuchi Tomonori、Sasaki Takehiko
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 13257-13257
  • DOI: 10.1038/s41598-019-49744-3
  • Peer Reviewed / Open Access
• [Presentation] Saturated fatty acid promotes prostate cancer development with tumor infiltrating regulatory T cell alteration in a Pten-deficient mouse model. (2022)
  • Author(s): Sato H., Narita S., Takahashi Y., Ishida M., Kashima S., Yamamoto R., Koizumi A., Nara T., Huang M., Numakura K., Saito M., Yoshioka T., Habuchi T.
  • Organizer: The 117th Annual Meeting of the American Urological Association
  • Int'l Joint Research
• [Presentation] Specific Gut Microbial Environment in Lard Diet-Induced Prostate Cancer Development and Progression. (2022)
  • Author(s): Sato H., Narita S., Takahashi Y., Ishida M., Kashima S., Yamamoto R., Koizumi A., Nara T., Huang M., Numakura K., Saito M., Yoshioka T., Habuchi T.
  • Organizer: 第81回日本癌学会総会
• [Presentation] The impact of specific fat-diets and obesity on prostate cancer initiation and progression using two different immunocompetent mouse models (2020)
  • Author(s): Sato H, Narita S, Yamamoto R, Koizumi A, Nara T, Kanda S, Numakura K, Saito M, Inoue T, Satoh S, Yoshioka T, Habuchi T
  • Organizer: The 35th Annual EAU congress
  • Int'l Joint Research
• [Presentation] PTENノックアウト前立腺癌マウスモデルにおいてラード食は全身炎症と腸内細菌叢の変化を介して前立腺癌進展を促進する (2020)
  • Author(s): 佐藤博美，成田伸太郎，山本竜平，小泉淳，奈良健平，神田壮平，沼倉一幸，齋藤満，井上 高光，佐藤滋，吉岡年明，羽渕友則
  • Organizer: 第24回腸内細菌学会
• [Presentation] 2種の免疫応答性マウスモデルにおける特定の脂肪食が前立腺 癌発症・進展に及ぼす影響 (2020)
  • Author(s): 佐藤博美，成田伸太郎，山本竜平，小泉淳，奈良健平，沼倉一幸，齋藤満，佐藤滋，吉岡 年明，羽渕友則
  • Organizer: 第79回日本癌学会総会
• [Presentation] 肝細胞におけるHeregulin産生の機序についての検討 (2019)
  • Author(s): 吉岡 年明, 南條 博, 大森 泰文
  • Organizer: 第124回 日本解剖学会総会