TET family proteins and 5-hydroxymethylcytosine in gastrointestinal carcinoma.

• Project/Area Number: 26461953
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: Kumamoto University
• Principal Investigator: MIYANARI Nobutomo 熊本大学, 医学部附属病院, 非常勤診療医師 (90336230)
• Co-Investigator(Kenkyū-buntansha): 馬場 祥史 熊本大学, 大学院生命科学研究部(医), 講師 (20599708) ; 志垣 博信 熊本大学, 医学部附属病院, 非常勤診療医師 (30594874) ; 渡邊 雅之 公益財団法人がん研究会, 有明病院 消化器外科, 部長 (80254639)
• Research Collaborator: MURATA Asuka 熊本大学, 医学部附属病院, 非常勤診療医師 (10625768)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: DNA脱メチル化機構 / 5-hmC発現低下 / TET酵素減少 / LINE-1メチル化レベル / 5－hmC / 脱メチル化 / TET酵素 / 食道癌 / 癌化 / 5-hmC

Outline of Final Research Achievements

The Ten-eleven translocation (TET) enzymes (TET1, TET2, and TET3) are implicated in DNA demethylation, through dioxygenase activity that converts 5′-cytosine methylation (5-methylcytosine [5-mC]) to 5-hydroxymethylcytosine (5-hmC). We evaluated functions of 5-hmC and TET expression in esophageal squamous cell carcinoma (ESCC). ELISA and immunohistochemical testing showed 5-hmC levels were significantly lower in ESCC than in paired normal tissues (P < 0.0001). TET2 expression was significantly lower in ESCCs than paired normal tissues (P < 0.0001), and significantly associated with 5-hmC levels in ESCCs (P = 0.003, r = 0.33). 5-hmC levels were also significantly associated with LINE-1 methylation level (P = 0.0002, r = 0.39). Patients with low 5-hmC levels had shorter overall survival than those with higher levels, although not significantly so (P = 0.084). In conclusion, TET2 reduction and subsequent 5-hmC loss might affect ESCC development and progression.

Research Products

• [Journal Article] Epigenetic field cancerization in gastrointestinal cancers. (2016)
  • Author(s): Baba Y, Ishimoto T, Kurashige J, Iwatsuki M, Sakamoto Y, Yoshida N, Watanabe M, Baba H.
  • Journal Title: Cancer Lett. Volume: 375(2) Issue: 2 Pages: 360-6
  • DOI: 10.1016/j.canlet.2016.03.009
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] TET family proteins and 5-hydroxymethylcytosine in esophageal squamous cell carcinoma. (2015)
  • Author(s): Murata A, Baba Y, Ishimoto T, Miyake K, Kosumi K, Harada K, Kurashige J, Iwagami S, Sakamoto Y, Miyamoto Y, Yoshida N, Yamamoto M, Oda S, Watanabe M, Nakao M, Baba H
  • Journal Title: Oncotarget Volume: 6（27） Issue: 27 Pages: 23372-82
  • DOI: 10.18632/oncotarget.4281
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] LINE-1 Methylation Level and Patient Prognosis in a Database of 208 Hepatocellular Carcinomas (2015)
  • Author(s): Harada K, Baba Y, Ishimoto T, Chikamoto A, Kosumi K, Hayashi H, Nitta H, Hashimoto D, Beppu T, Baba H
  • Journal Title: Ann Surg Oncol Volume: 22(4) Issue: 4 Pages: 1280-7
  • DOI: 10.1245/s10434-014-4134-3
  • Peer Reviewed
• [Journal Article] Relationship between LINE-1 hypomethylation and Helicobacter pylori infection in gastric mucosae (2015)
  • Author(s): Kosumi K, Baba Y, Ishimoto T, Harada K, Miyake K, Izumi D, Tokunaga R, Murata A, Eto K, Sugihara H, Shigaki H, Iwagami S, Sakamoto Y, Miyamoto Y, Yoshida N, Watanabe M, Komohara Y, Takeya M, Baba H
  • Journal Title: Med Oncol Volume: 32(4) Issue: 4 Pages: 571-571
  • DOI: 10.1007/s12032-015-0571-5
  • Peer Reviewed
• [Journal Article] IGF2 DMR0 methylation, loss of imprinting, and patient prognosis inesophageal squamous cell carcinoma (2014)
  • Author(s): A. Murata, Y. Baba, M. Watanabe, H. Shigaki, K. Miyake, T. Ishimoto, M. Iwatsuki, S. Iwagami, N. Yoshida, E. Oki, M. Morita, M. Nakao, and H. Baba.
  • Journal Title: Ann. Surg. Oncol. Volume: 21 Issue: 4 Pages: 1166-1174
  • DOI: 10.1245/s10434-013-3414-7
  • Peer Reviewed / Open Access
• [Journal Article] Clinical implications of the LINE-1 methylation levels in patients with gastrointestinal cancer (2013)
  • Author(s): Baba Y, Murata A, Watanabe M, Baba H
  • Journal Title: Surg Today Volume: (Epub ahead of print) Issue: 10 Pages: 1807-1816
  • DOI: 10.1007/s00595-013-0763-6
  • Peer Reviewed