The molecular mechanisms of colon carcinogenesis in C57BL/KsJ-db/db-Apc mice

• Project/Area Number: 25860529
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Gifu University
• Principal Investigator: KUBOTA MASAYA 岐阜大学, 医学(系)研究科(研究院), 特任助教 (90542407)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 大腸癌化学予防 / 肥満関連大腸発癌 / 大腸癌 / 化学予防 / 肥満

Outline of Final Research Achievements

In this study, the chemopreventive effects of therapeutic agents for lifestyle disease or phytochemicals, and its underlying molecular mechanisms were investigated using obesity- and lifestyle disease-related colon cancer models. Metformin, an agent for diabetes, and green tea catechin decreased the number of intestinal tumors in diabetic db/db-Min/+ mice. Besides, astaxanthin, one of phytochemicals, and captopril, an antihypertensive agent, suppressed colonic precancerous lesions in different models. In addition, metformin and astaxanthin prevented the development of liver tumors in obese diabetic mice through the improvement of oxidative stress and chronic inflammation. Thus, these results suggest that certain phytochemicals or therapeutic agents for lifestyle disease may become effective candidates for the chemoprevention of colon carcinogenesis. Clinical trials testing the efficacy of those agents in obese diabetic individuals will be ready to start in our facility.

Research Products

• [Journal Article] Sodium alginate prevents progression of non-alcoholic steatohepatitis and liver carcinogenesis in obese and diabetic mice. (2016)
  • Author(s): Miyazaki T, Shirakami Y, Kubota M, Ideta T, Kochi T, Sakai H, Tanaka T, Moriwaki H, Shimizu M.
  • Journal Title: Oncotarget Volume: - Issue: 9 Pages: 10448-10458
  • DOI: 10.18632/oncotarget.7249
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Preventive effects of astaxanthin on diethylnitrosamine-induced liver tumorigenesis in C57/BL/KsJ-db/db obese mice. (2016)
  • Author(s): Ohno T, Shimizu M, Shirakami Y, Miyazaki T, Ideta T, Kochi T, Kubota M, Sakai H, Tanaka T, Moriwaki H.
  • Journal Title: Hepatol Res. Volume: 46(3) Issue: 3 Pages: 201-209
  • DOI: 10.1111/hepr.12550
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Pentoxifylline prevents non-alcoholic steatohepatitis-related liver pre-neoplasms by inhibiting hepatic inflammation and lipogenesis. (2015)
  • Author(s): Shirakami Y, Shimizu M, Kubota M, Ohno T, Kochi T, Nakamura N, Sumi T, Tanaka T, Moriwaki H, Seishima M.
  • Journal Title: Eur J Cancer Prev Volume: 25 Issue: 3 Pages: 206-215
  • DOI: 10.1097/cej.0000000000000172
  • Peer Reviewed
• [Journal Article] Metformin suppresses diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-+Leprdb/+Leprdb mice. (2015)
  • Author(s): Shimizu M, Ohno T, Shirakami Y, Baba A, Kochi T, Kubota M, Tsurumi H, Tanaka T, Moriwaki H.
  • Journal Title: PLoS One Volume: 10 Issue: 4 Pages: e0124081-e0124081
  • DOI: 10.1371/journal.pone.0124081
  • Peer Reviewed / Open Access
• [Journal Article] Chemopreventive potential of green tea catechins in hepatocellular carcinoma. (2015)
  • Author(s): Shimizu M, Shirakami Y, Sakai H, Kubota M, Kochi T, Ideta T, Miyazaki T, Moriwaki H.
  • Journal Title: Int J Mol Sci. Volume: 16(3) Issue: 3 Pages: 6124-6139
  • DOI: 10.3390/ijms16036124
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Inhibitory effects of astaxanthin on azoxymethane-induced colonic preneoplastic lesions in C57/BL/KsJ- db/db mice. (2014)
  • Author(s): Kochi T, Shimizu M, Sumi T, Kubota M, Shirakami Y, Tanaka T, Moriwaki H.
  • Journal Title: BMC Gastroenterol Volume: 14 Pages: 212-212
  • Peer Reviewed / Open Access
• [Journal Article] Chemoprevention of colorectal cancer by targeting obesity-related metabolic abnormalities. (2014)
  • Author(s): Shirakami Y, Shimizu M, Kubota M, Araki H, Tanaka T, Moriwaki H, Seishima M.
  • Journal Title: World J Gastroenterol Volume: 20 Pages: 8939-8946
  • Peer Reviewed
• [Journal Article] Preventive effects of the angiotensin-converting enzyme inhibitor, captopril, on the development of azoxymethane-induced colonic preneoplastic lesions in diabetic and hypertensive rats. (2014)
  • Author(s): Kochi T, Shimizu M, Ohno T, Baba A, Sumi T, Kubota M, Shirakami Y, Tsurumi H, Tanaka T, Moriwaki H.
  • Journal Title: Oncol Lett Volume: 8 Pages: 223-229
  • Peer Reviewed
• [Journal Article] Combination of Bevacizumab and Acyclic Retinoid Inhibits the Growth of Hepatocellular Carcinoma Xenografts (2014)
  • Author(s): Kubota M, Shimizu M, Baba A, Ohno T, Kochi T, Shirakami Y, Moriwaki H.
  • Journal Title: Journal of Nutritional Science and Vitaminology Volume: 60 Issue: 5 Pages: 357-362
  • DOI: 10.3177/jnsv.60.357
  • NAID: 130004773635
  • ISSN: 0301-4800, 1881-7742
  • Peer Reviewed
• [Journal Article] Non-alcoholic steatohepatitis and preneoplastic lesions develop in the liver of obese and hypertensive rats: Suppressing effects of EGCG on the development of liver lesions. (2014)
  • Author(s): Kochi T, Shimizu M, Terakura D, Baba A, Ohno T, Kubota M, Shirakami Y, Tsurumi H, Tanaka T, Moriwaki H.
  • Journal Title: Cancer Lett Volume: 342 Issue: 1 Pages: 60-69
  • DOI: 10.1016/j.canlet.2013.08.031
  • Peer Reviewed
• [Journal Article] Synergistic growth inhibition by acyclic retinoid and phosphatidylinositol 3-kinase inhibitor in human hepatoma cells. (2013)
  • Author(s): Baba A, Shimizu M, Ohno T, Shirakami Y, Kubota M, Kochi T, Terakura D, Tsurumi H, Moriwaki H.
  • Journal Title: BMC Cancer Volume: 13 Issue: 1 Pages: 465-465
  • DOI: 10.1186/1471-2407-13-465
  • Peer Reviewed
• [Journal Article] Enhanced development of azoxymethane-induced colonic preneoplastic lesions in hypertensive rats. (2013)
  • Author(s): Takahiro Kochi, Masahito Shimizu, Tomohiko Ohno, Atsushi Baba, Takafumi Sumi, Masaya Kubota, Yohei Shirakami, Hisashi Tsurumi, Takuji Tanaka, and Hisataka Moriwaki
  • Journal Title: Int. J. Mol. Sci. Volume: 14 Issue: 7 Pages: 14700-14711
  • DOI: 10.3390/ijms140714700
  • Peer Reviewed
• [Presentation] ベバシツマブと非環式レチノイドの併用による肝癌細胞増殖抑制効果に関する検討 (2013)
  • Author(s): 久保田全哉、清水雅仁、馬場厚、寺倉大志、大野智彦、河内隆宏、白上洋平、森脇久隆
  • Organizer: 第49回日本肝臓学会総会
  • Place of Presentation: 京王プラザホテル
• [Presentation] Nutraceutical approach による肥満・NASH関連肝腫瘍形成の抑制‐分岐鎖アミノ酸（BCAA）および緑茶カテキン（EGCG）を用いた検討‐ (2013)
  • Author(s): 久保田 全哉、清水 雅仁、河内 隆宏、大野 智彦、白上 洋平、森脇 久隆
  • Organizer: 第40回日本肝臓学会西部会
  • Place of Presentation: 長良川国際会議場