To identify the molecular mechanism underlying colorectal cancer progression via RNF43

• Project/Area Number: 17K10639
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kumamoto University
• Principal Investigator: Hdetaka Sugihara 熊本大学, 病院, 非常勤診療医師 (10608863)
• Co-Investigator(Kenkyū-buntansha): 石本 崇胤 熊本大学, 病院, 特任准教授 (00594889) ; 今井 克憲 熊本大学, 大学院生命科学研究部(医), 助教 (60555746) ; 今村 裕 公益財団法人がん研究会, 有明病院 消化器外科, 医長 (70583045)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 大腸癌 / Wntシグナル / RNF43 / RNF43遺伝子 / Wnt シグナル

Outline of Final Research Achievements

We identified the clinical significance of RNF43 mutations in a large Japanese cohort and the role of RNF43 at various stages of colorectal cancer development and progression. Patients with colorectal cancer harbouring mutated RNF43 experienced a higher recurrence rate than those harbouring non-mutated RNF43. We generated Rnf43 knockout mice. An azoxymethane/dextran sodium sulphate mouse model demonstrated that tumours were markedly larger in Rnf43 knockout mice than in wild-type mice.
These findings provide evidence that Wnt signalling activation by RNF43 mutations during the tumourigenic stage enhances tumour growth and promotes a high recurrence rate in colorectal cancer patients.

Academic Significance and Societal Importance of the Research Achievements

本研究ではRNF43 knockout マウスを用いて消化管上皮および大腸腫瘍進展における RNF43発現意義を明らかにしてきた。
大腸 癌においてAPCやβ-cateninのmutationを介した増殖・進展機構に関する報告は数多く認める が、RNF43のmutationや発現低下が腫瘍増大・進展に与える影響について明らかにすることは学術的意義の大きいところといえる。

Research Products

• [Journal Article] Impact of loss-of-function mutations at the RNF43 locus on colorectal cancer development and progression (2018)
  • Author(s): Eto T, Miyake K, Nosho K, Ohmuraya M, Imamura Y, Arima K, Kanno S, Fu L, Kiyozumi Y, Izumi D, Sugihara H, Hiyoshi Y, Miyamoto Y, Sawayama H, Iwatsuki M, Baba Y, Yoshida N, Furukawa T, Araki K, Baba H, Ishimoto T
  • Journal Title: The Journal of Pathology Volume: 245 Issue: 4 Pages: 445-455
  • DOI: 10.1002/path.5098
  • Peer Reviewed
• [Journal Article] Activation of Transforming Growth Factor Beta 1 Signaling in Gastric Cancer-associated Fibroblasts Increases Their Motility, via Expression of Rhomboid 5 Homolog 2, and Ability to Induce Invasiveness of Gastric Cancer Cells. (2017)
  • Author(s): Ishimoto T, Miyake K, Nandi T, Yashiro M, Onishi N, Huang KK, Joyce LN, Kalpana R, Tay ST, Suzuki Y, Cho BC, Kuroda D, Arima K, Izumi D, Iwatsuki M, Baba Y, Oki E, Watanabe M, Saya H, Hirakawa K, Baba H, Tan P.
  • Journal Title: Gastroenterology Volume: in press Issue: 1 Pages: 191-204
  • DOI: 10.1053/j.gastro.2017.03.046
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Potential of a cure in patients with colorectal liver metastases and concomitant extrahepatic disease. (2017)
  • Author(s): Imai K, Castro Benitez C, Allard MA, Vibert E, Sa Cunha A, Cherqui D, Castaing D, Bismuth H, Baba H, Adam R
  • Journal Title: J Surg Oncol. Volume: 115(4) Issue: 4 Pages: 488-496
  • DOI: 10.1002/jso.24539
  • Peer Reviewed
• [Journal Article] Long-term outcomes of radiofrequency ablation combined with hepatectomy compared with hepatectomy alone for colorectal liver metastases. (2017)
  • Author(s): Imai K, Allard MA, Castro Benitez C, Vibert E, Sa Cunha A, Cherqui D, Castaing D, Baba H, Adam R.
  • Journal Title: Br J Surg. Volume: 104(5) Issue: 5 Pages: 570-579
  • DOI: 10.1002/bjs.10447
  • Peer Reviewed
• [Presentation] Impact of loss-of-function mutations at the RNF43 locus on colorectal cancer progression (2018)
  • Author(s): Ishimoto T, Eto T, Miyake K, Fu L, Uchihara T, Arima K, Yasuda T, Itoyama R, Yoshida N, Baba H
  • Organizer: SGICC 2018
  • Int'l Joint Research
• [Presentation] Functional role of Ring Finger Protein 43 in intestinal stem cells during colorectal tumorigenesis (2017)
  • Author(s): Eto T, Ishimoto T, Oda E, Kuroda D, Arima K, Ohuchi M, Nakamura K, Sawayama H, Kinoshita K, Iwatsuki M, Baba Y, Sakamoto Y, Yoshida N, Baba H.
  • Organizer: AACR Annual Meeting 2017
  • Int'l Joint Research
• [Presentation] 大腸癌進展における Ring Finger Protein 43（RNF43）の機能解析 (2017)
  • Author(s): 江藤二男、石本崇胤、内原智之、織田絵里、問端輔、八木泰佑、黒田大介、有馬浩大、大内繭子、中村健一、澤山浩、木下浩一、岩槻政晃、馬場祥史、坂本快郎、吉田直矢、馬場秀夫
  • Organizer: 第117 回日本外科学会定期学術集会
• [Presentation] 大腸癌におけるRing Finger Protein 43 発現と腫瘍発育進展の検討 (2017)
  • Author(s): 江藤二男、石本崇胤、内原智幸、八木泰佑、黒田大介、澤山浩、日吉幸晴、岩槻政晃、馬場祥史、宮本 裕士、吉田 直矢、馬場 秀夫
  • Organizer: 第 28 回消化器癌発生学会