Luminal epithelium integrity and the EMT

2015 Fiscal Year Final Research Report

• Project Area: Regulation of polarity signaling during morphogenesis, remodeling, and breakdown of epithelial tubular structure
• Project/Area Number: 23112008
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Hokkaido University
• Principal Investigator: Sabe Hisataka 北海道大学, 医学(系)研究科(研究院), 教授 (40187282)
• Co-Investigator(Kenkyū-buntansha): ONEYAMA Chitose 愛知県がんセンター研究所, 感染腫瘍学部, 部長 (90373208)
• Project Period (FY): 2011-04-01 – 2016-03-31
• Keywords: 乳癌 / 腎名細胞がん / 癌間充識悪性 / 薬剤耐性 / p53変異 / メバロン酸合成経路 / Arf6 / LPA

Outline of Final Research Achievements

Drug resistance and high motility of cancer are central to malignancies. These phenotypes often emerge coupled with the mesenchymal programs. Arf6 and its effector AMAP1 are often overexpressed in various cancers, and promote invasion and metastasis. We first found that AMAP1 binds to EPB41L5, which is normally expressed in mesenchymes to promote focal adhesion dynamics. Thus, the Arf6 pathway appears to be a cancer-specific mesenchymal pathway. Moreover, the mevalonate pathway (MVP) was essential to Arf6 activation, via geranylgeranyl transferase-II and its substrate Rab11b. Mutant-p53s promoted Arf6 activation, via enhancing MVP. Besides receptor tyrosine kinases, G-protein-coupled receptor for LPA also directly activated Arf6. We finally demonstrated that the overexpressed Arf6 pathway promotes drug resistance. Our results showed that the Arf6-based pathway is critical to cancer malignancies and drug resistance, and provide excellent therapeutic opportunities.

Free Research Field

医歯薬学