Elucidation of the mechanism of RCC malignant transformation using renal tubule specific SAV1 knockout mice

2018 Fiscal Year Final Research Report

• Project/Area Number: 15K08348
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Oita University
• Principal Investigator: MATSUURA KEIKO 大分大学, 医学部, 教授 (00291542)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: 腎癌 / 悪性化 / ノックアウトマウス / SAV1

Outline of Final Research Achievements

SAV1 is a core component of the Hippo pathway. To analyze its implication in malignant transformation of clear cell renal cell carcinoma (ccRCC), I generated kidney-specific SAV1- or SAV1 and VHL-knockout mice. I observed many renal cysts in kidneys of SAV1 knockout mice. Renal tubular epithelial cells showed high cellularity and multiple layering, including enlargement of their nuclei. Furthermore, VHL deletion combined with SAV1 deletion was likely to inhibit cellular abnormalities shown in SAV1 knockout mice, although double knockout mice were rarely generated. These results suggest that SAV1 plays important roles for regulation of nuclear size of renal epithelial cells, and the maintenance of renal structure under physiological conditions.

Free Research Field

医歯薬学

Academic Significance and Societal Importance of the Research Achievements

腎癌の動物モデルとして、本研究では腎尿細管に特異的なSAV1欠失により、細胞異型や細胞増殖、腎発生の異常が認められた。つまり、腫瘍抑制に働くHippoパスウェイが、VHL-HIF1パスウェイ以外でも腎の発生や癌化に関わることを初めて明らかにした。また、Hippoパスウェイがin vivoでどのように他のパスウェイと関係するかをパスウェイ解析やVHLとのダブルノックアウトマウスによって明らかにした。したがって、新たな腎発生や癌化のメカニズムの発見だけでなく、既存の分子標的治療薬がターゲットとしているVHL-HIF1パスウェイでは根治し得ない高悪性度腎癌の治療開発の礎となった。