Novel mechanisms that cause cancers due to the abnormality of Wnt signal network

2020 Fiscal Year Final Research Report

• Project/Area Number: 16H06374
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Tumor biology
• Research Institution: Osaka University
• Principal Investigator: Kikuchi Akira 大阪大学, 医学系研究科, 教授 (10204827)
• Project Period (FY): 2016-05-31 – 2021-03-31
• Keywords: Wnt / ARL4C / DKK1 / CAKP4 / GREB1 / Wnt5a / 微小環境 / 腫瘍

Outline of Final Research Achievements

Wnts are secretory proteins which are essential for organogenesis during the embryonic period. After birth, Wnt signaling activated by Wnt ligands are involved in maintaining organ homeostasis. It is known that abnormal activation of Wnt signaling due to gene alterations of its components causes cancer, however, its molecular mechanisms are not fully understood and development of anti-cancer drugs has not yet been progressed. In this research, we analyzed the roles of new Wnt signaling-related molecules and pathways that we identified in tumorigenesis. We elucidated their mechanisms using cultured cells and model mice and clarified clinical significance using human specimens and databases. Furthermore, we developed anti-sense oligo nucleotides and antibodies against the molecules we found and we showed their efficacy of cancer therapy using model mice.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

Wntシグナルの異常による新規の細胞がん化の分子基盤を確立できたことが本研究の学術的意義である。具体的には、新規のWntシグナル関連経路としてARL4C経路、DKK1-CKAP4経路、GREB1経路を見出し、これらのシグナル経路による腫瘍形成の分子機構を明らかにした。
また、炎症を伴ったがん組織において、Wnt5aがどの線維芽細胞に発現されるかを特定して、分泌されたWnt5aが腫瘍形成を誘導する分子機構を示した。本研究成果は、がん細胞の多様な増殖や転移の分子機構の理解の進展に寄与するとともに、新たながん診断法の確立や抗がん剤開発の端緒となったために、社会的意義は大きい。