The roles of Lats1/2 kinases in a stepwise EMT-MET switching mechanism of malignant tumor cells.

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K07167
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Osaka University
• Principal Investigator: Yabuta Norikazu 大阪大学, 微生物病研究所, 准教授 (10343245)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 口腔扁平上皮癌 / 上皮間葉転換 / 細胞増殖 / 悪性化 / Hippo経路 / LATS / リン酸化 / TGF-β

Outline of Final Research Achievements

The epithelial-to-mesenchymal transition (EMT) is an essential process by which cancer cells acquire malignant features. However, the molecular mechanism and functional implications of the EMT and the mesenchymal-to-epithelial transition (MET) in tumor progression remain unclear. In this study, two aggressive cancer cell lines, mesenchymal-like Delta-SAS and epithelial-like SAS-δ, were established from oral cancer cells. SAS-δ, but not parental SAS, exhibited piled-up overgrowth and invasive tumor formation in the tongues of nude mice, suggesting that SAS-δ represented more advanced cancer cells than the parental SAS cells. The EMT-related transcriptional factor SLUG is phosphorylated by the Hippo pathway-related kinases, LATS1 and LATS2, and knockdown of SLUG by siRNA promoted the invasive activity of SAS-δ. Our results suggest that LATS1/2-SLUG axis regulates the transition of SAS cells to the advanced stage via repeated switching between the EMT and MET.

Free Research Field

分子細胞生物学

Academic Significance and Societal Importance of the Research Achievements

癌治療における最大の障壁は癌細胞の進展（悪性化）による浸潤・転移と、薬剤耐性能や放射線耐性能を獲得した癌幹細胞に由来するとされる癌の再発である。上皮間葉転換（EMT）と間葉上皮転換（MET）は浸潤転移や幹細胞化を誘導するため、悪性癌細胞の成り立ちや分子機序を理解する上で重要な細胞内機構の一つである。本研究の成果は、癌細胞がEMTとMETを連続的に繰り返すことによりさらに悪性度が高い癌細胞に形質転換する分子機構を解明し、これを標的とした新しい癌診断法や画期的な治療法の開発に繋がるものである。