Investigation of novel molecular targeted therapeutics based on epigenetics in colorectal cancer.

• Project/Area Number: 16K19943
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Kumamoto University (2017-2018); Japanese Foundation for Cancer Research (2016)
• Principal Investigator: TOKUNAGA Ryuma 熊本大学, 医学部附属病院, 非常勤診療医師 (20594881)
• Research Collaborator: BABA Hideo
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 大腸癌 / マイクロRNA / 細胞周期 / 血管新生 / 上皮間葉転換 / 化学療法 / JMJD3 / エピジェネティクス / EZH2

Outline of Final Research Achievements

We showed for the first time that JMJD3 low expression in colorectal cancer was a poor prognostic factor and that JMJD3 regulated p15INK4b to suppress tumor progression. In addition, miR186-5p was identified as a microRNA which suppressed JMJD3 from the result of a microRNA array. Furthermore, we found that miR186-5p suppressed apoptosis, promoted cell cycle, and increased proliferation in colorectal cancer cell, and confirmed that the expression levels of miR186-5p and JMJD3 are inversely correlated in clinical samples. However, no significant correlation was detected between the expression level of miR186-5p and the patient prognosis or tumor progression status.

Academic Significance and Societal Importance of the Research Achievements

大腸癌は本邦における癌罹患数および臓器別癌死亡数で上位を占め、世界的に研究がすすめられている癌腫である。我々は大腸癌におけるエピジェネティクスを標的とした新規分子標的治療薬を開発することを目標として本研究を行った。今まで大腸癌におけるJumonji-domain containing 3 (JMJD3)の役割については報告がなく、今回の研究においてmiR186-5pがJMJD3を制御すること、および癌の進展に関わっていることを初めて示すことができた。これはmiR186-5pやJMJD3をターゲットとした新規治療薬の開発につながる可能性がある。

Research Products

• [Journal Article] Monitoring sputum culture in resected esophageal cancer patients with preoperative treatment. (2017)
  • Author(s): Kosumi K, Baba Y, Yamashita K, Ishimoto T, Nakamura K, Ohuchi M, Kiyozumi Y, Izumi D1, Tokunaga R, Harada K, Shigaki H, Kurashige J, Iwatsuki M, Sakamoto Y, Yoshida N, Watanabe M, Baba H
  • Journal Title: Dis Esophagus. Volume: 30(12) Pages: 1-9
  • DOI: 10.1093/dote/dox092
  • Peer Reviewed
• [Journal Article] Colorectal cancer: epigenetic alterations and their clinical implications. (2017)
  • Author(s): Puccini A, Berger MD, Naseem M, Tokunaga R, Battaglin F, Cao S, Hanna DL, McSkane M, Soni S, Zhang W, Lenz HJ
  • Journal Title: Biochim Biophys Acta Volume: 1868(2) Pages: 439-448
  • Peer Reviewed
• [Journal Article] Laparoscopic resection of a tumour in the ischiorectal fossa - a video vignette. (2017)
  • Author(s): Tokunaga R, Akiyoshi T, Hiyoshi Y, Fukunaga Y, Ueno M
  • Journal Title: Colorectal Dis Volume: 19(8) Pages: 787-788
  • DOI: 10.1111/codi.13806
  • Peer Reviewed
• [Journal Article] Comparison of systemic inflammatory and nutritional scores in colorectal cancer patients who underwent potentially curative resection. (2017)
  • Author(s): Tokunaga R, Sakamoto Y, Nakagawa S, Izumi D, Kosumi K, Taki K, Higashi T, Miyata T, Miyamoto Y, Yoshida N, Baba H.
  • Journal Title: Int J Clin Oncol. Volume: in press Pages: 740-748
  • DOI: 10.1007/s10147-017-1102-5
  • Peer Reviewed
• [Journal Article] CONUT: a novel independent predictive score for colorectal cancer patients undergoing potentially curative resection. (2017)
  • Author(s): Tokunaga R, Sakamoto Y, Nakagawa S, Ohuchi M, Izumi D, Kosumi K, Taki K, Higashi T, Miyamoto Y, Yoshida N, Oki E, Watanabe M, Baba H
  • Journal Title: Int J Colorectal Dis Volume: 32(1) Pages: 99-106
  • DOI: 10.1007/s00384-016-2668-5
  • Peer Reviewed
• [Journal Article] The utility of tumor marker combination, including serum P53 antibody, in colorectal cancer treatment. (2017)
  • Author(s): Tokunaga R, Sakamoto Y, Nakagawa S, Yoshida N, Baba H
  • Journal Title: Surg Today Volume: 47(5) Pages: 636-642
  • DOI: 10.1007/s00595-016-1464-8
  • Peer Reviewed
• [Journal Article] Cancer-related multiple brain infarctions caused by Trousseau syndrome in a patient with metastatic colon cancer: a case report. (2016)
  • Author(s): Akiyama T, Miyamoto Y, Sakamoto Y, Tokunaga R, Kosumi K, Shigaki H, Kurashige J, Iwatsuki M, Baba Y, Yoshida N, Baba H
  • Journal Title: Surg Case Rep. Volume: 2(1) Pages: 91-91
  • DOI: 10.1186/s40792-016-0217-7
  • Peer Reviewed
• [Journal Article] Prognostic and clinical impact of PIK3CA mutation in gastric cancer: pyrosequencing technology and literature review. (2016)
  • Author(s): Harada K, Baba Y, Shigaki H, Ishimoto T, Miyake K, Kosumi K, Tokunaga R, Izumi D, Ohuchi M, Nakamura K, Kiyozumi Y, Kurashige J, Iwatsuki M, Miyamoto Y, Sakamoto Y, Yoshida N, Watanabe M, Baba H.
  • Journal Title: BMC Cancer. Volume: 16 Pages: 400-400
  • DOI: 10.1186/s12885-016-2422-y
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic and clinical impact of sarcopenia in esophageal squamous cell carcinoma. (2016)
  • Author(s): Harada K, Ida S, Baba Y, Ishimoto T, Kosumi K, Tokunaga R, Izumi D, Ohuchi M, Nakamura K, Kiyozumi Y, Imamura Y, Iwatsuki M, Iwagami S, Miyamoto Y, Sakamoto Y, Yoshida N, Watanabe M, Baba H.
  • Journal Title: Dis Esophagus. Volume: 29(6) Pages: 627-33
  • DOI: 10.1111/dote.12381
  • Peer Reviewed
• [Journal Article] Tumor/normal esophagus ratio in (18)F-fluorodeoxyglucose positron emission tomography/computed tomography for response and prognosis stratification after neoadjuvant chemotherapy for esophageal squamous cell carcinoma. (2016)
  • Author(s): Izumi D, Yoshida N, Watanabe M, Shiraishi S, Ishimoto T, Kosumi K, Tokunaga R, Taki K, Higashi T, Harada K, Miyata T, Ida S, Imamura Y, Iwagami S, Baba Y, Sakamoto Y, Miyamoto Y, Yamashita Y, Baba H
  • Journal Title: J Gastroenterol. Volume: 51(8) Pages: 788-95
  • DOI: 10.1007/s00535-015-1150-4
  • Peer Reviewed
• [Journal Article] APOBEC3B is an enzymatic source of molecular alterations in esophageal squamous cell carcinoma. (2016)
  • Author(s): Kosumi K, Baba Y, Ishimoto T, Harada K, Nakamura K, Ohuchi M, Kiyozumi Y, Izumi D, Tokunaga R, Taki K, Higashi T, Miyata T, Shigaki H, Kurashige J, Hiyoshi Y, Iwatsuki M, Iwagami S, Sakamoto Y, Miyamoto Y, Yoshida N, Oki E, Watanabe M, Baba H
  • Journal Title: Med Oncol. Volume: 33(3) Pages: 26-26
  • DOI: 10.1007/s12032-016-0739-7
  • Peer Reviewed
• [Journal Article] Omental flap after pelvic exenteration for pelvic cancer. (2016)
  • Author(s): Miyamoto Y, Akiyama T, Sakamoto Y, Tokunaga R, Ohuchi M, Shigaki H, Kurashige J, Iwatsuki M, Baba Y, Yoshida N, Baba H.
  • Journal Title: Surg Today Volume: 46(12) Pages: 1471-1475
  • DOI: 10.1007/s00595-016-1348-y
  • Peer Reviewed
• [Journal Article] Orbital Apex Syndrome Caused by Invasive Aspergillosis as an Adverse Effect of Systemic Chemotherapy for Metastatic Colorectal Cancer: a Case Report. (2016)
  • Author(s): Miyamoto Y, Sakamoto Y, Ohuchi M, Tokunaga R, Shigaki H, Kurashige J, Iwatsuki M, Baba Y, Yoshida N, Watanabe M, Baba H
  • Journal Title: Anticancer Res. Volume: 36(2) Pages: 821-3
  • Peer Reviewed
• [Journal Article] Retroileal colorectal anastomosis after extended left colectomy: application for laparoscopic surgery. (2016)
  • Author(s): Sakamoto Y, Tokunaga R, Miyamoto Y, Ohuchi M, Nakamura K, Kosumi K, Harada K, Shigaki H, Kurashige J, Iwatsuki M, Baba Y, Yoshida N, Baba H.
  • Journal Title: Surg Today. Volume: 46(12) Pages: 1476-1478
  • DOI: 10.1007/s00595-016-1313-9
  • Peer Reviewed
• [Journal Article] Fibroblast growth factor receptor 2 expression, but not its genetic amplification, is associated with tumor growth and worse survival in esophagogastric junction adenocarcinoma. (2016)
  • Author(s): Tokunaga R, Imamura Y, Nakamura K, Ishimoto T, Nakagawa S, Miyake K, Nakaji Y, Tsuda Y, Iwatsuki M, Baba Y, Sakamoto Y, Miyamoto Y, Saeki H, Yoshida N, Oki E, Watanabe M, Oda Y, Bass AJ, Maehara Y, Baba H.
  • Journal Title: Oncotarget. Volume: in press Pages: 19748-61
  • DOI: 10.18632/oncotarget.7782
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The Prognostic Significance of Histone Lysine Demethylase JMJD3/KDM6B in Colorectal Cancer (2016)
  • Author(s): Tokunaga R, Sakamoto Y, Nakagawa S, Miyake K, Izumi D, Kosumi K, Taki K, Higashi T, Imamura Y, Ishimoto T, Iwatsuki M, Baba Y, Miyamoto Y, Yoshida N, Oki E, Watanabe M, Baba H.
  • Journal Title: Ann Surg Oncol Volume: 23(2) Pages: 678-85
  • DOI: 10.1245/s10434-015-4879-3
  • Peer Reviewed
• [Journal Article] Duration of Smoking Cessation and Postoperative Morbidity After Esophagectomy for Esophageal Cancer: How Long Should Patients Stop Smoking Before Surgery? (2016)
  • Author(s): Yoshida N, Baba Y, Hiyoshi Y, Shigaki H, Kurashige J, Sakamoto Y, Miyamoto Y, Iwatsuki M, Ishimoto T, Kosumi K, Sugihara H, Harada K, Tokunaga R, Izumi D, Watanabe M, Baba H.
  • Journal Title: World J Surg Volume: 40(1) Pages: 142-7
  • DOI: 10.1007/s00268-015-3236-9
  • Peer Reviewed / Open Access
• [Journal Article] Risk factors of early recurrence within 6 months after esophagectomy following neoadjuvant chemotherapy for resectable advanced esophageal squamous cell carcinoma. (2016)
  • Author(s): Yoshida N, Baba Y, Shigaki H, Harada K, Iwatsuki M, Sakamoto Y, Miyamoto Y, Kurashige J, Kosumi K, Tokunaga R, Watanabe M, Baba H
  • Journal Title: Int J Clin Oncol Volume: 21(6) Pages: 1071-1078
  • DOI: 10.1007/s10147-016-0994-9
  • Peer Reviewed
• [Journal Article] Effect of Esophagus Position on Surgical Difficulty and Postoperative Morbidities After Thoracoscopic Esophagectomy. (2016)
  • Author(s): Yoshida N, Baba Y, Shigaki H, Shiraishi S, Harada K, Watanabe M, Iwatsuki M, Kurashige J, Sakamoto Y, Miyamoto Y, Ishimoto T, Kosumi K, Tokunaga R, Yamashita Y, Baba H
  • Journal Title: Semin Thorac Cardiovasc Surg Volume: 28(1) Pages: 172-9
  • DOI: 10.1053/j.semtcvs.2015.12.002
  • Peer Reviewed
• [Journal Article] Incidence and risk factors of synchronous colorectal cancer in patients with esophageal cancer: an analysis of 480 consecutive colonoscopies before surgery. (2016)
  • Author(s): Yoshida N, Tamaoki Y, Baba Y, Sakamoto Y, Miyamoto Y, Iwatsuki M, Shono T, Miyamoto H, Imuta M, Kurashige J, Sawayama H, Tokunaga R, Watanabe M, Sasaki Y, Yamashita Y, Baba H.
  • Journal Title: Int J Clin Oncol Volume: 6 Pages: 1079-1084
  • DOI: 10.1007/s10147-016-1015-8
  • Peer Reviewed
• [Presentation] miR 186-5p はヒストン脱メチル化酵素JMJD3/KDM6Bの抑制を介し大腸癌における腫瘍増殖を促進させる (2016)
  • Author(s): 徳永 竜馬、坂本 快郎、大内 繭子、中村 健一、 美馬 浩介、澤山 浩、木下 浩一、辛島 龍一、 岩槻 政晃、馬場 祥史、宮本 裕士、吉田 直矢、 馬場 秀夫
  • Organizer: 第27回日本消化器癌発生学会総会
  • Place of Presentation: 城山観光ホテル（鹿児島県）