Development of novel therapeutics and multidisciplinary strategies for colorectal cancer based on epithelial-to-mesenchymal transition

• Project/Area Number: 17K10660
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Miyagi Prefectural Hospital Organization Miyagi Cancer Center
• Principal Investigator: Miura Koh 地方独立行政法人宮城県立病院機構宮城県立がんセンター(研究所), がん薬物療法研究部, 特任研究員 (40282074)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 上皮間葉転換 / 大腸癌 / 同所性移植モデル / Serpini1 / CHST11 / 抗がん剤開発 / 新規治療法 / 集学的治療

Outline of Final Research Achievements

To further promote our research (Sasaki H, et al. Cancer Sci. 2008 Apr;99(4):7 11-9.; Matsuda Y, et al. Cancer Sci. 2016 May;107(5):619-28.) and to develop novel therapeutics for refractory colorectal cancer through functional analyses of genes regulating epithelial-to-mesenchymal transition (EMT), we performed functional analyses of the EMT-associated genes such as Serpini1 and CHST11. With Western blotting, we clarified that SERPINI1 protein in supernatants suppressed the expression of E-cadherin in colorectal cancer cells with EMT phenotype such as SW620. The same results were found in COLO320 as well. On the other hand, similar results were not found in colorectal cancer cells such as HT-29, SW948, T84, LoVo, HCT8, HCT15, and DLD-1. This analysis is also ongoing on CHST11. We also analyzed immunohistochemical staining of SERPINI1 and CHST11 in orthotopic mice models of human colorectal cancer cells.

Academic Significance and Societal Importance of the Research Achievements

大腸癌を含む上皮系悪性腫瘍は、本来の上皮細胞が形質転換することで発生しますが、その過程で間葉系細胞の特性を獲得してくることがあり（上皮間葉転換；epithelial-to-mesenchymal transition: EMT）、癌がさらに浸潤、転移する機能を獲得して癌治療を困難にすることが知られています。私たちはこれまでの先行研究において、大腸癌におけるEMT関連遺伝子を明らかにし、解析を続けてきました。難治性の大腸癌そのほかの悪性腫瘍の新しい治療につなげることを目的として、この研究を続けています。

Research Products

• [Journal Article] Associations of Japanese food intake with survival of stomach and colorectal cancer: a prospective patient cohort study (2020)
  • Author(s): Minami Yuko、Kanemura Seiki、Oikawa Tomoyuki、Suzuki Shinichi、Hasegawa Yasuhiro、Nishino Yoshikazu、Fujiya Tsuneaki、Miura Koh
  • Journal Title: Cancer Science Volume: - Issue: 7 Pages: 2558-2569
  • DOI: 10.1111/cas.14459
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of oral administration of cystine and theanine in colorectal cancer patients undergoing capecitabine-based adjuvant chemotherapy after surgery: a multi-institutional, randomized, double-blinded, placebo-controlled, phase II trial (JORTC-CAM03) (2019)
  • Author(s): Hamaguchi Reo、Tsuchiya Takashi、Miyata Go、Sato Toshihiko、Takahashi Kenichi、Miura Koh、Oshio Hiroshi、Ohori Hisatsugu、Ariyoshi Keisuke、Oyamada Shunsuke、Iwase Satoru
  • Journal Title: Supportive Care in Cancer Volume: - Issue: 8 Pages: 3649-3657
  • DOI: 10.1007/s00520-019-05205-1
  • Peer Reviewed / Open Access
• [Journal Article] Loss of protein phosphatase 6 in mouse keratinocytes enhances K-ras G12D -driven tumor promotion (2018)
  • Author(s): Kurosawa Koreyuki、Inoue Yui、Kakugawa Yoichiro、Yamashita Yoji、Kanazawa Kosuke、Kishimoto Kazuhiro、Nomura Miyuki、Momoi Yuki、Sato Ikuro、Chiba Natsuko、Suzuki Mai、Ogoh Honami、Yamada Hidekazu、Miura Koh、Watanabe Toshio、Tanuma Nobuhiro、Tachi Masahiro、Shima Hiroshi
  • Journal Title: Cancer Science Volume: 109 Issue: 7 Pages: 2178-2187
  • DOI: 10.1111/cas.13638
  • Peer Reviewed / Open Access
• [Journal Article] Associations of cigarette smoking and alcohol drinking with stomach cancer survival: A prospective patient cohort study in Japan (2018)
  • Author(s): Minami Yuko、Kanemura Seiki、Oikawa Tomoyuki、Suzuki Shinichi、Hasegawa Yasuhiro、Miura Koh、Nishino Yoshikazu、Kakugawa Yoichiro、Fujiya Tsuneaki
  • Journal Title: International Journal of Cancer Volume: - Issue: 5 Pages: 1072-1085
  • DOI: 10.1002/ijc.31408
  • Peer Reviewed / Open Access
• [Journal Article] Pyruvate kinase type M2 contributes to the development of pancreatic ductal adenocarcinoma by regulating the production of metabolites and reactive oxygen species (2018)
  • Author(s): Yokoyama Misa、Tanuma Nobuhiro、Shibuya Rie、Shiroki Takeharu、Abue Makoto、Yamamoto Kuniharu、Miura Koh、Yamaguchi Kazunori、Sato Ikuro、Tamai Keiichi、Satoh Kennichi
  • Journal Title: International Journal of Oncology Volume: 52 Pages: 881-891
  • DOI: 10.3892/ijo.2018.4258
  • Peer Reviewed
• [Journal Article] Enhanced expression of PKM2 is involved in the gastric cancer development via regulating cancer specific metabolism. (2017)
  • Author(s): Shiroki T, Yokoyama M, Tanuma N, Maejima R, Tamai K, Yamaguchi K, Oikawa T, Noguchi T, Miura K, Fujiya T, Shima H, Sato I, Kamiya N, Hatakeyama M, Iijima K, Shimosegawa T and Satoh K.
  • Journal Title: Cancer Science Volume: 印刷中 Issue: 5 Pages: 931-940
  • DOI: 10.1111/cas.13211
  • Peer Reviewed / Open Access
• [Journal Article] Drug delivery of oral anti-cancer fluoropyrimidine agents. (2017)
  • Author(s): Miura K, Shima H, Takebe N, Julie R, Satoh K, Kakugawa Y, Satoh M, Kinouchi M, Yamamoto K, Hasegawa Y, Kawai M, Kanazawa K, Fujiya T, Unno M and Katakura R.
  • Journal Title: Expert Opin.Drug Deliv Volume: 印刷中 Issue: 12 Pages: 1-12
  • DOI: 10.1080/17425247.2017.1316260
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ex vivo model of non-small cell lung cancer using mouse lung epithelial cells. (2017)
  • Author(s): Sato T, Morita M, Tanaka R, Inoue Y, Nomura M, Sakamoto Y, Miura K, Ito S, Sato I, Tanaka N, Abe J, Takahashi S, Kawai M, Sato M, Hippo Y, Shima H, Okada Y, Tanuma N
  • Journal Title: Oncol Lett. Volume: 14(6) Pages: 6863-6868
  • DOI: 10.3892/ol.2017.7098
  • Peer Reviewed / Open Access