Elucidation of PLXND1-mediated EMT mechanism in colorectal cancer

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K18117
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Osaka University
• Principal Investigator: Hagihara Kiyotaka 大阪大学, 医学系研究科, 招へい教員 (30781778)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 上皮間葉移行 / 大腸癌

Outline of Final Research Achievements

We investigated the mechanism of epithelial-mesenchymal transition (EMT), a mechanism of distant metastasis of colorectal cancer. We found that PLXND1 knockdown decreased cell invasion and migration, increased sensitivity to chemotherapy, and decreased mesenchymal markers. SEMA3E is the ligand of PLXND1 and FURIN which is involved in the activity of SEMA3E was inhibited and mesenchymal markers were decreased. Next, using PLXND1 knockdown and FURIN inhibitor, we performed signal analysis of EMT changes. We found that phosphorylated PI3K and AKT were decreased in both ways. That indicated PLXND1-mediated EMT is mediated through PI3K/AKT. The relationship between Notch signal and FURIN could not be clarified.

Free Research Field

大腸癌

Academic Significance and Societal Importance of the Research Achievements

StageⅣ大腸癌の5年生存率は20.2%と、大腸癌死亡には遠隔転移が大きく関わり、遠隔転移機構である上皮間葉移行の制御が重要である。PLXND1を阻害することでEMTを抑制し、浸潤能や遊走能を低下させ、化学療法への感受性を亢進させることが明らかとなった。PLXND1を直接阻害することは困難であるがFURIN阻害を用いリガンドであるSEMA3Eの活性を阻害することでPLXND1を間接的に阻害することが可能となる。FURIN阻害剤は実用化には至っていないが、近年sh RNAによるFURIN阻害の研究が進んでおり、大腸癌のEMT制御に応用できる可能性がある。