Role of Smurf2-YY1 axis in regulating colorectal cancer metastasis

• Project/Area Number: 20K17640
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Chiba University
• Principal Investigator: Sato Nami 千葉大学, 大学院医学研究院, 特任助教 (40867272)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: YY1 / 大腸癌 / 転移 / ITGAV / ITGB1 / 肝転移 / Smurf2 / E3リガーゼ

Outline of Research at the Start

当教室では現在ユビキチン-プロテアソーム系E3リガーゼSmad-ubiquitination regulatory factor2(Smurf2)に関し研究を進めている。E3リガーゼは高い基質特異性をもつため新規治療標的として期待される。近年、Smurf2がUPSを介してYY1をdegradationすることが報告された。YY1はNFkB/YY1/Snail loopを介して上皮間葉移行(EMT)を誘導し転移促進的に働くことが知られている。本研究では大腸癌肝転移におけるSmurf2-YY1 axisの機能解明を行い、EMT制御に焦点をあてた新たな治療戦略を構築する一助としたい。

Outline of Final Research Achievements

The aim of this study was to investigate the possibility that the ubiquitin proteasome system (UPS) E3 ligase Smurf2 acts as a tumor suppressor in colorectal cancer by degrading the transcription factor YY1 through the UPS and suppressing the epithelial-mesenchymal transition (EMT).
Contrary to the hypothesis, the relationship between Smurf2, YY1, and EMT was considered to be low in the examination using clinical specimens and cell lines. However, further analysis of YY1 function revealed that it has a tumor-suppressive role by suppressing colon cancer cell migration and invasion. Furthermore, microarray analysis confirmed that YY1 down-regulated ITGAV and ITGB1 genes, which are integrin family members related to cell adhesion and cancer metastasis.

Academic Significance and Societal Importance of the Research Achievements

残念ながらUPS系やEMTに焦点をあてた大腸癌の転移メカニズム解明という目的は果たせなかった。一方で、大腸癌においてYY1がITGAVとITGB1の遺伝子発現を調節することで腫瘍抑制的役割を果たすことを示唆するデータはこれまで報告されておらず、新たな知見である。今後さらなる検証を重ねることで大腸癌の新たな転移機構を解明する一助になることが期待される。

Research Products

• [Journal Article] Tumor-suppressive role of Smad ubiquitination regulatory factor 2 in patients with colorectal cancer (2022)
  • Author(s): Sato N, Sakai N, Furukawa K, Takayashiki T, Kuboki S, Takano S, Ohira G, Miyauchi H, Matsubara H, Ohtsuka M.
  • Journal Title: Scientific reports Volume: 12 Issue: 1 Pages: 5495-5495
  • DOI: 10.1038/s41598-022-09390-8
  • Peer Reviewed / Open Access
• [Journal Article] Yin Yang 1 regulates ITGAV and ITGB1, contributing to improved prognosis of colorectal cancer (2022)
  • Author(s): Sato Nami、Sakai Nozomu、Furukawa Katsunori、Takayashiki Tsukasa、Kuboki Satoshi、Takano Shigetsugu、Ohira Gaku、Matsubara Hisahiro、Ohtsuka Masayuki
  • Journal Title: Oncology Reports Volume: 47 Issue: 5 Pages: 1791-2431
  • DOI: 10.3892/or.2022.8298
  • Peer Reviewed / Open Access
• [Presentation] 転写因子YY1はITGAV,ITGB1の遺伝子発現を調節し大腸癌細胞の遊走と浸潤を抑制することで大腸癌患者の予後に寄与する (2022)
  • Author(s): 佐藤 菜実、酒井望、古川勝規、高屋敷吏、久保木知、高野重紹 鈴木大亮、細川勇、三島敬、西野仁恵、大塚将之
  • Organizer: 日本外科学会