Tumor-suppressive role of Smad ubiquitination regulatory factor 2 in patients with colorectal cancer

Research Project

Project/Area Number	19K09164
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 55020:Digestive surgery-related
Research Institution	Chiba University
Principal Investigator	Sakai Nozomu 千葉大学, 医学部附属病院, 助教 (70436385)
Co-Investigator(Kenkyū-buntansha)	古川勝規千葉大学, 大学院医学研究院, 准教授 (00400987) 高屋敷吏千葉大学, 大学院医学研究院, 講師 (30456024) 久保木知千葉大学, 大学院医学研究院, 講師 (50571410) 大塚将之千葉大学, 大学院医学研究院, 教授 (90334185) 賀川真吾千葉県がんセンター(研究所), 肝胆膵外科, 主任医長 (90507302)
Project Period (FY)	2019-04-01 – 2022-03-31
Project Status	Completed (Fiscal Year 2021)
Budget Amount *help	¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000) Fiscal Year 2021: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000) Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000) Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Keywords	転移 / 浸潤 / 癌幹細胞 / 細胞遊走能 / Cancer stemness / 上皮-間葉移行
Outline of Research at the Start	本研究は、現在我々がターゲットとしているKLF5の上流調節因子としてのユビキチンE3リガーゼSmurf2 (Smad ubiquitination regulatory factor 2)に注目し、消化器癌、主に大腸直腸癌肝転移の細胞増殖、浸潤、遊走能、EMT等、癌の悪性度ひいては患者の予後につながる癌進展の各過程における機能解析、制御機構の解明を目的とする。
Outline of Final Research Achievements	Smad ubiquitination regulatory factor 2 (Smurf2) plays various roles in cancer progression. However, the correlation between Smurf2 and clinical outcomes has not been determined in patients with colorectal cancer and colorectal liver metastases. We analyzed 66 patients with colorectal cancer who developed liver metastases. Smurf2 expression was assessed using immunohistochemical analysis of primary and metastatic liver tumors. High Smurf2 expression in both primary and metastatic tumors was significantly associated with longer overall survival time and time to surgical failure. Multivariate analyses revealed that low Smurf2 expression in primary tumors was an independent predictor of poor prognosis. In vitro experiments demonstrated that knockdown of Smurf2 increased cell migration and tumor sphere formation. Western blot analyses revealed that Smurf2 knockdown increased the protein expression of EpCAM.Smurf2 can be considered a positive biomarker of cancer stem cell-like properties.
Academic Significance and Societal Importance of the Research Achievements	転移、再発は癌患者の予後を規定する重要な因子である。本研究では、ユビキチンリガーゼのひとつであるSmurf2に注目し、Smurf2が癌細胞のstemnessに関与する重要な因子であることが分かった。今後、Smurf2を新たなターゲットとして、これを制御することで新規治療法の開発につながる可能性がある。