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: 徳永 竜馬 熊本大学, 医学部附属病院, 非常勤診療医師 (20594881)
• 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: JMJD3 / 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 / エピジェネティクス / EZH2

Outline of Annual Research Achievements

Jumonji-domain containing 3 (JMJD3) はEnhancer of Zeste Homolog 2（EZH2）が特異的にメチル化するヒストン3リジン27(H3K27)の脱メチル化酵素であり、p16INK4aを再活性化させることでがん細胞の増殖を抑制することが報告されている。我々は、JMJD3が大腸癌患者において正常部で高発現であり、その大腸癌局所での低発現は予後不良因子であること、および癌抑制遺伝子p15INK4bを制御し大腸癌進展を抑制するメカニズムを初めて明らかにした。また、マイクロRNAアレイの結果から2種類のmiRを検出し、in vitroにてJMJD3を抑制するmiRとしてmiR186-5pを同定した。大腸癌細胞株においてmiR186-5pを強制発現させたところ、JMJD3の発現およびCDH1、VASH1、TFAP2Eといった大腸癌における重要な遺伝子の発現抑制を確認できた。過剰発現を行い、controlと比較することで現象の変化 (MTT assayにて増殖能、PI染色・AnnexinⅤ染色・FACS解析にて細胞周期、等)に及ぼす影響を確認したところ、miR186-5pは大腸癌細胞のアポトーシスを抑制し、細胞周期をすすめ、増殖能を上げることがわかった。また、public databaseを用いてmiR186-5pとJMJD3の発現量の関連を確認したところ、逆相関するという結果であった。そのため、さらに当科保有の臨床サンプルを用いてmiR186-5pの発現量と予後や臨床病理学的因子との関連を検索したが、仮説と異なり、miR186-5pの発現量は予後や腫瘍進行度と有意な相関関係は認めなかった。以上より研究は比較的順調に進行していたが、in vitroのデータと臨床サンプルを用いた結果の理論的整合性を認めなかった。

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] Neutrophil/lymphocyte ratio predicts the prognosis in esophageal squamous cell carcinoma patients. (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, Kurashige J, Hiyoshi Y, Iwagami S, Sakamoto Y, Miyamoto Y, Yoshida N, Watanabe M, Baba H.
  • Journal Title: Surg Today Volume: 46(4) Pages: 405-13
  • DOI: 10.1007/s00595-015-1197-0
  • 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] Preoperative Nutritional Assessment by Controlling Nutritional Status (CONUT) is Useful to estimate Postoperative Morbidity After Esophagectomy for Esophageal Cancer. (2016)
  • Author(s): Yoshida N, Baba Y, Shigaki H, Harada K, Iwatsuki M, Kurashige J, Sakamoto Y, Miyamoto Y, Ishimoto T, Kosumi K, Tokunaga R, Imamura Y, Ida S, Hiyoshi Y, Watanabe M, Baba H
  • Journal Title: World J Surg Volume: 40(8) Pages: 1910-7
  • DOI: 10.1007/s00268-016-3549-3
  • Peer Reviewed
• [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）