Elucidation of molecular mechanisms regulating cell competition and contact inhibition

2020 Fiscal Year Final Research Report

• Project/Area Number: 18H03994
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 44:Biology at cellular to organismal levels, and related fields
• Research Institution: Kyoto University (2019-2020); Hokkaido University (2018)
• Principal Investigator: Fujita Yasuyuki 京都大学, 医学研究科, 教授 (50580974)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 接触阻害 / 上皮多層化 / COL17A1 / CD44

Outline of Final Research Achievements

By performing a series of screenings targeting plasma membrane proteins, we have found that COL17A1 and CD44 accumulate in RasV12-, Src-, or ErbB2-transformed epithelial cells. We further demonstrate that the expression of COL17A1 and CD44 is profoundly upregulated at the upper layers of multilayered, transformed epithelia in vitro and in vivo. The accumulated COL17A1 and CD44 suppress mitochondrial membrane potential and ROS production. The diminished intracellular ROS level then promotes resistance against ferroptosis-mediated cell death upon cell extrusion, thereby positively regulating the formation of multilayered structures. Moreover, we demonstrate that CD44 regulates membrane accumulation of COL17A1 in multilayered structures. These results suggest that CD44 and COL17A1 are crucial regulators for the clonal expansion of transformed cells within multilayered epithelia, thus being potential targets for early diagnosis and preventive treatment for precancerous lesions.

Free Research Field

分子腫瘍学

Academic Significance and Societal Importance of the Research Achievements

今回の我々の研究によって、上皮多層化のプロセスにCOL17A1とCD44が重要な役割を果たしていることが明らかになった。COL17A1とCD44が上皮の多層化というこれまでがん診断・治療の対象になっていなかったプロセスの標的分子となる可能性を示している。今後は、多くのヒト前がん病変におけるCOL17A1とCD44の発現を調べるとともに、これらのin vivoにおける前がん病変形成への機能的関与を詳細に調べていく。