The association between SORL1 and advanced bladder cancer

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K23899
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0901:Oncology and related fields
• Research Institution: Toho University
• Principal Investigator: UTSUMI Takanobu 東邦大学, 医学部, 助教 (80594275)
• Project Period (FY): 2019-08-30 – 2021-03-31
• Keywords: 膀胱癌 / SORL1 / ROCK / cofilin

Outline of Final Research Achievements

The expression of SORL1 in bladder cancer cell lines was confirmed by Western blotting, and SORL1 was knock-out by CRISPR-Cas9 method. SORL1 knock-out cells showed significantly increased migration and invasion ability, and Western blotting showed that the loss of SORL1 resulted in increased ROCK1 and ROCK2 expression. The loss of SORL1 caused an increase in ROCK1 and ROCK2 expression, suggesting that LIMK-mediated phosphorylation of cofilin predominates in SORL1 knockout cells, leading to F-actin polymerization.
Treatment with the ROCK inhibitor Y-27632 significantly decreased the migration and invasion ability of SORL1 knock-out cells. The ROCK inhibitor Y-27632 significantly decreased the migration and invasion ability of SORL1 knock-out cells, and the expression of phosphorylated cofilin was also decreased, suggesting that F-actin was cleaved and depolymerized.

Free Research Field

泌尿器腫瘍

Academic Significance and Societal Importance of the Research Achievements

進行性膀胱癌に対する薬物療法は白金製剤を中心とした化学療法のみであったが、2016年以降転移性尿路上皮癌の二次治療薬としてFDAに承認されてから、免疫チェックポイント阻害剤が一定の治療効果を示している。しかしながら、その奏効率はおおむね25～30%であり、新規の治療標的やバイオマーカーとなり得る分子の探索が求められている。
本研究では膀胱癌におけるSORL1の基礎的な機能解析を行い、SORL1の喪失がROCK/LIMK/cofilinシグナルを介して膀胱癌の進展に関与していることが判明し、ROCK阻害剤により進展を抑制できることが判明した。進行性膀胱癌治療への応用の可能性が示唆された。