• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Modulation of AMPK/ TET2/ 5-hmC axis in response to metabolic alterations as a novel pathway for obesity-related colorectal cancer development

Research Project

Project/Area Number 19K17389
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 53010:Gastroenterology-related
Research InstitutionYamagata University

Principal Investigator

KON TAKASHI  山形大学, 医学部, 客員研究員 (10829740)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
KeywordsTET2 / 5-hmC / 大腸癌 / 肥満 / AMPK / メタボリックシンドローム / エピゲノム / 5hmc / 5hmC
Outline of Research at the Start

なぜ肥満やMetSが大腸発がんを引き起こすのか、その直接的な分子機序は不明な点が多い。近年、細胞内のエネルギーセンサーであるAMPKを介した腫瘍抑制因子TET2の活性調節がDNAのエピジェネティック修飾を制御し、高血糖状態における発がんに促進的に作用することが報告され、TET2は肥満、MetSによる大腸発がんに深く関与している可能性がある。本研究では、ヒトのゲノムや組織、動物モデル、細胞株を用い、肥満関連大腸がんにおけるTET2の変異解析やTET2の発現レベルとその不安定性に関する機序を解析することで、肥満、MetSからの大腸がんを直接的に結び付ける分子メカニズムを明らかにする。

Outline of Final Research Achievements

Obesity has been widely acknowledged to pose a great risk of colorectal cancer (CRC). A recent study demonstrated that sustained hyperglycemia destabilizes the tumor suppressor ten-eleven translocation (TET) 2 as a substrate of the AMPK and dysregulates levels of 5-hydroxymethylcytosine (5-hmC). This novel pathway may play important roles in obesity-related CRC development.
In this study, we demonstrated that the expression of 5-hmC and TET2 was decreased in obesity-related CRC tissue. Glucose and insulin treatment decreased the expression of TET2 in CRC cells. The proliferation was induced in CRC cells by TET2siRNA transfection. In contrast, induction of AMPK inhibited cell proliferation accompanied by the upregulation of TET2 expression. AMPK-TET2-5-hmC axis is proposed as novel molecular pathway in obesity-related CRC development, may be a new diagnostic marker and therapeutic target.

Academic Significance and Societal Importance of the Research Achievements

本邦で増加している肥満関連大腸癌に肥満やメタボリックシンドロームの増加に伴って本邦では大腸癌が増加しています。この肥満に関連した大腸癌の発生機序を明らかにすることで、この大腸がんの増加に歯止めをかけ、また有効な治療や予防法を開発できると考えます。本研究の結果から肥満関連大腸発がんにAMPK-TET2という新しい経路がかかわっていることが考えられ、これは新しい診断マーカーや治療標的になる可能性があります。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (5 results)

All 2021 2020

All Journal Article (1 results) Presentation (4 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] 肥満、メタボリックシンドロームと消化管病態の関連性2020

    • Author(s)
      佐々木悠,阿部靖彦,八木周,水本尚子,今孝志,小野里祐介,堺貴之,梅原松樹,伊藤南,上野義之
    • Journal Title

      消化器・肝臓内科

      Volume: 8 Pages: 341-348

    • Related Report
      2020 Research-status Report
  • [Presentation] Insulin and glucose altered AMPK-TET2-5hmC axis toward on the obesity-related colorectal cancer development2021

    • Author(s)
      Takashi Kon, Yu Sasaki, Yasuhiko Abe, Yusuke Onozato, Makoto Yagi, Naoko Mizumoto, Takayuki Sakai, Matsuki Umehara, Minamin Ito, Ayumi Koseki, Yoshiyuki Ueno
    • Organizer
      DDW 2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 肥満関連大腸癌におけるTET2遺伝子発現の検討2021

    • Author(s)
      今 孝志、佐々木 悠、阿部 靖彦、小野里 祐介、八木 周、水本 尚子、堺 貴之、伊藤 南、梅原 松樹、小関 歩、上野 義之
    • Organizer
      第107回 日本消化器病学会総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Obesity and colorectal neoplasm: identifying obesity-associated somatic genomic signals from colorectal adenoma and carcinoma2020

    • Author(s)
      Takashi Kon, Yu Sasaki, Yasuhiko Abe, Takao Yaoita, Makoto Yagi, Naoko Mizumoto, Masakuni Shoji, Yusuke Onozato, Takayuki Sakai, Ayumi Koseki, Hidenori Sato, Yoshiyuki Ueno
    • Organizer
      DDW 2020
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] 肥満関連大腸腫瘍における遺伝子変化の特徴についての検討2020

    • Author(s)
      今孝志,佐々木悠,阿部靖彦,小野里祐介,佐藤秀則,矢尾板孝夫,八木周,水本尚子,東海林正邦,堺貴之,小関歩,上野義之
    • Organizer
      第62回日本消化器病学会大会
    • Related Report
      2020 Research-status Report

URL: 

Published: 2019-04-18   Modified: 2023-01-30  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi