Crosstalk between activated Notch and inactivated TGF-beta signaling in cancer cells

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K16765
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Chiba University
• Principal Investigator: MANO Yasunobu 千葉大学, 未来医療教育研究センター, 特任助教 (80577362)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 癌 / Notchシグナル / TGF-βシグナル

Outline of Final Research Achievements

Activated Ras and inactivated TGF-β signaling have been observed in various cancer such as pancreatic, colorectal, and gastric cancer. However, these crosstalk mechanisms of carcinogenesis remain not completely understood. In this study, we focused the tumor suppressor mechanism of Notch signaling, downstream of Ras and performed RNA-Seq and Time-lapse analysis to identify the molecular mechanism of cooperation between Notch and TGF-β signaling in cancer cells. As a result, JAG1 overexpression(OE) and TGFBR2 knockdown(KD) caused repression of p21 and p15, leading to bypass of JAG1-induced senescence. Moreover, we observed that normal cells were induced senescence in co-culture with JAG1-OE and TGFBR2-KD cells and normal cells.

Free Research Field

癌エピゲノム

Academic Significance and Societal Importance of the Research Achievements

Notchシグナルは、癌においては発癌性及び抗腫瘍性の両面性を持つ可能性が示唆されているが、今回の解析によって、癌細胞ではTGF-βシグナルの不活化やp53の変異などにより癌抑制的に機能しないが、周囲の正常細胞では増殖抑制的に機能する事が明らかになった。即ち癌細胞自身は老化せず、周囲の正常細胞を老化させていた。癌細胞はこの機構を巧みに利用して浸潤・転移を加速させている可能性があり、非常に興味深い結果である。将来的にさらに感度の高いGSIやNotchリガンドを阻害する分子標的薬が開発されれば、Notchシグナルを標的とした癌治療の臨床応用ヘの可能性もあり得るのではないかと考える。