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

• 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
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
• 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.

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。

Research Products

• [Journal Article] Clinicopathological study of 5 cases of renal cell carcinoma with t(6;11)(p21;q12). (2017)
  • Author(s): Kuroda N, Yorita K, Sasaki N, Ishihara A, Matsuura K, Daa T, Mori S, Sasaki A, Mikami S, Shigematsu K, Nagashima Y.
  • Journal Title: Pol J Pathol. Volume: 68(1) Pages: 66-72
  • DOI: 10.5114/pjp.2017.67617
  • Peer Reviewed / Open Access
• [Journal Article] Overexpression of cannabinoid receptor 1 in esophageal squamous cell carcinoma is correlated with metastasis to lymph nodes and distant organs, and poor prognosis. (2017)
  • Author(s): Hijiya N, Shibata T, Daa T, Hamanaka R, Uchida T, Matsuura K, Tsukamoto Y, Nakada C, Iha H, Inomata M, Moriyama M.
  • Journal Title: Pathol Int. Volume: 67 Issue: 2 Pages: 83-90
  • DOI: 10.1111/pin.12495
  • Peer Reviewed / Open Access
• [Journal Article] Kidney-specific knockout of Sav1 in the mouse promotes hyper-proliferation of renal tubular epithelium through suppression of the Hippo pathway. (2016)
  • Author(s): Kai T, Tsukamoto Y, Hijiya N, Tokunaga A, Nakada C, Uchida T, Daa T, Iha H, Takahashi M, Nomura T, Sato F, Mimata H, Ikawa M, Seto M, Matsuura K, Moriyama M.
  • Journal Title: J Pathol. Volume: 印刷中 Issue: 1 Pages: 97-108
  • DOI: 10.1002/path.4706
  • Peer Reviewed / Open Access
• [Journal Article] Downregulation of WDR20 due to loss of 14q is involved in the malignant transformation of clear cell renal cell carcinoma. (2016)
  • Author(s): Takahashi M, Tsukamoto Y, Kai T, Tokunaga A, Nakada C, Hijiya N, Uchida T, Daa T, Nomura T, Sato F, Mimata H, Matsuura K, Moriyama M.
  • Journal Title: Cancer Science Volume: 107(4) Issue: 4 Pages: 417-423
  • DOI: 10.1111/cas.12892
  • Peer Reviewed / Open Access
• [Presentation] Genetic deletion of SAV1 enhances proliferation and nuclear irregularity in renal tubular epithelial cells (2016)
  • Author(s): Tomoki Kai, Keiko Matsuura, Yoshiyuki Tsukamoto, Mika Takahashi,Naoki Hijiya, Fuminori Sato, Masatsugu Moriyama, Hiromitsu Mimata
  • Organizer: American Urological Association's 2016
  • Place of Presentation: San Diego Convention Center(San Diego, CA)
  • Year and Date: 2016-05-10
  • Int'l Joint Research
• [Presentation] Identification of WDR20 as a new tumor suppressor gene preferentially altered in high-grade clear cell renal cell carcinoma (2016)
  • Author(s): Mika Takahashi, Tomoki Kai, Akinori Tokunaga,Takeo Nomura,Fuminori Sato, Keiko Matsuura, Masatsugu Moriyama, Hiromitsu Mimata
  • Organizer: American Urological Association's 2016
  • Place of Presentation: San Diego Convention Center(San Diego, CA)
  • Year and Date: 2016-05-10
  • Int'l Joint Research
• [Presentation] WDR20は淡明細胞型腎細胞癌の悪性化に関与する (2016)
  • Author(s): 高橋 美香, 松浦 恵子, 甲斐 友喜, 徳永 暁憲, 佐藤 文憲, 三股 浩光, 守山 正胤
  • Organizer: 第104回 日本泌尿器科学会総会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-04-25
• [Presentation] 腎特異的ノックアウトマウスモデルにおいて、SAV1 lossはHippo pathwayの抑制により腎尿細管上皮細胞に過剰増殖をもたらす (2016)
  • Author(s): 甲斐 友喜, 松浦 恵子, 塚本 善之, 高橋 美香, 中田 知里, 内田 智久, 泥谷 直樹, 佐藤 文憲, 守山 正胤, 三股 浩光
  • Organizer: 第104回 日本泌尿器科学会総会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-04-23
• [Presentation] WDR20は淡明型腎細胞癌の悪性化に関与する (2016)
  • Author(s): 高橋美香、松浦恵子、甲斐友喜、徳永暁憲、佐藤文憲、守山正胤、三股浩光
  • Organizer: 第25回 泌尿器科分子・細胞研究会
  • Place of Presentation: ハイアットリージェンシー大阪（大阪府大阪市）
  • Year and Date: 2016-02-26
• [Presentation] 腎尿細管特異的ノックアウトマウスモデルにおいて、SAV1 lossはHippo pathwayの抑制により腎尿細管上皮細胞に過剰増殖・核の大型化をもたらす (2016)
  • Author(s): 甲斐友喜、松浦恵子、塚本善之、高橋美香、中田知里、内田智久、泥谷直樹、佐藤文憲、守山正胤、三股浩光
  • Organizer: 第25回 泌尿器科分子・細胞研究会
  • Place of Presentation: ハイアットリージェンシー大阪（大阪府大阪市）
  • Year and Date: 2016-02-26
• [Presentation] Re-expression of SAV1 inhibits renal tumor growth in vivo through downregulation of TGF beta pathway (2015)
  • Author(s): Tomoki Kai, Keiko Matsuura, Naoki Hijiya, Fuminori Sato, Takashi Kobayashi, Masatsugu Moriyama, Hiromitsu Mimata
  • Organizer: 第67回 西日本泌尿器科学会総会
  • Place of Presentation: 福岡国際会議場(福岡県福岡市)
  • Year and Date: 2015-11-05
• [Presentation] WDR20 is involved in the malignant transformation of clear cell renal cell carcinoma (ccRCC) (2015)
  • Author(s): Mika Takahashi, Keiko Matsuura, Tomoki Kai, Akihiro Tokunaga, Fuminori Sato, Masatsugu Moriyama, Hiromitsu Mimata
  • Organizer: 第67回 西日本泌尿器科学会総会
  • Place of Presentation: 福岡国際会議場(福岡県福岡市)
  • Year and Date: 2015-11-05
• [Presentation] Re-expression of SAV1 inhibits Renal Tumor Growth in vivo (2015)
  • Author(s): Tomoki Kai, Keiko Matsuura, Chisato Nakada, Yoshiyuki Tsukamoto, Naoki Hijiya, Fuminori Sato, Masatsugu Moriyama, Hiromitsu Mimata
  • Organizer: 35th CONGRESS OF THE SOCIETE INTERNATIONALE D’UROLOGIE
  • Place of Presentation: Melbourne Convention and Exhibition Centre（Melbourne, Australia）
  • Year and Date: 2015-10-15
  • Int'l Joint Research
• [Presentation] 腎細胞癌移植モデルにおいてSAV1はTGF-βpathwayを抑制することで腫瘍増生を阻害する (2015)
  • Author(s): 甲斐友喜、松浦恵子、泥谷直樹、佐藤文憲、小林隆志、守山正胤、三股浩光
  • Organizer: 第１０３回日本泌尿器科学会総会
  • Place of Presentation: 石川県立音楽堂(石川県金沢市)
  • Year and Date: 2015-04-18
• [Presentation] 淡明細胞型腎細胞癌(ccRCC)の悪性化に関与する遺伝子の探索 (2015)
  • Author(s): 高橋美香、松浦恵子、甲斐友喜、徳永暁憲、佐藤文憲、三股浩光、守山正胤
  • Organizer: 第１０３回日本泌尿器科学会総会
  • Place of Presentation: 石川県立音楽堂(石川県金沢市)
  • Year and Date: 2015-04-18