Generation of mouse models of renal cancer malignant transformation targeting Hippo pathway and therapeutic application

• Project/Area Number: 18K07070
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Oita University
• Principal Investigator: Matsuura Keiko 大分大学, 医学部, 教授 (00291542)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: Hippoパスウェイ / ノックアウトマウス / 腎癌 / 悪性化 / モデルマウス

Outline of Final Research Achievements

In this study, with the aim of creating a model that mimics the development and malignant transformation of renal cancer, I generated mice in which the Hippo pathway component SAV1 and the tumor suppressor gene VHL gene were knocked out in the kidney.
SAV1 homo-knockout mouse died soon after birth with reduced kidney weight and renal dysfunction. Histologically, these mice showed renal cyst formation with atypia, accompanied by activation of YAP. These renal cysts were histologically distinct from those in VHL homo-knockout mice. SAV1 and VHL double homo-knockout mice also died shortly after birth. Although none of these mice developed renal cancer, a mouse model for the development of atypical renal cysts was generated by inactivation of the Hippo pathway.

Academic Significance and Societal Importance of the Research Achievements

腎癌の発症と悪性化を模倣するモデルを作製し、新たな治療法の開発を目指した。腎発生異常をきたしたため、癌の発症には至らなかったが、新たに腎臓の正常発生にSAV1が関わっていることを証明できた。また異型を伴う腎嚢胞を形成するモデルマウスの作成ができたことから、異型を伴う腎嚢胞が持つ病態を解析する礎となる研究としての意義を持つと考える。

Research Products

• [Journal Article] Association between psychomotor function and ALDH2 genotype after consuming barley shochu: A randomized crossover trial (2023)
  • Author(s): Matsuura Keiko、Kushio Satoshi、Imai Hiromitsu、Kudo Hideo、Wakuda Hirokazu、Otani Naoyuki、Kuranari Masae、Sekiguchi Ai、Ohyama Tetsuji、Uemura Naoto
  • Journal Title: Clinical and Translational Science Volume: 16 Issue: 4 Pages: 686-693
  • DOI: 10.1111/cts.13482
  • Peer Reviewed / Open Access
• [Journal Article] Developmental Stages of Grassenema procaviae Petter, 1959 (Cosmocercoidea: Atractidae) Found in the Stomach of Cape Hyrax (Procavia capensis) (2022)
  • Author(s): Hasegawa Hideo、Hayashi Kei、Akita Yuko、Une Yumi、Huffman Michael A.、Matsuura Keiko
  • Journal Title: Journal of Parasitology Volume: 108 Issue: 4 Pages: 366-373
  • DOI: 10.1645/21-117
  • Peer Reviewed
• [Journal Article] Notes on morphology and life history of Probstmayria gombensis (Nematoda: Cosmocercoides: Atractidae), parasitic in eastern chimpanzees, Pan troglodytes schweinfurthii, in Bulindi, Uganda. (2021)
  • Author(s): Hasegawa H, McLennan MR, Huffman MA, Matsuura K.
  • Journal Title: J Parasitol Volume: 107(2) Issue: 2 Pages: 287-294
  • DOI: 10.1645/20-88
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A transgenic mouse expressing miR-210 in proximal tubule cells shows mitochondrial alteration: possible association of miR-210 with a shift in energy metabolism. (2020)
  • Author(s): Nakada C, Hijiya N, Tsukamoto Y, Yano S, Kai T, Uchida T, Kimoto M, Takahashi M, Daa T, Matsuura K, Shin T, Mimata H, Moriyama M.
  • Journal Title: J Pathol. Volume: in press Issue: 1 Pages: 12-25
  • DOI: 10.1002/path.5394
  • Peer Reviewed
• [Journal Article] irst description of male worms of Enterobius (Colobenterobius) serratus (Nematoda: Oxyuridae), the pinworm parasite of proboscis monkeys. (2020)
  • Author(s): Hasegawa H, Frias l, Peter S, Hasan NH, Stark DJ, Lynn MS, Sipangkui S, Goossens B, Matsuura K, Okamoto M, MacIntosh AJJ.
  • Journal Title: Zootaxa Volume: 4722(3) Issue: 3 Pages: 187-294
  • DOI: 10.11646/zootaxa.4722.3.6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nematodes belonging to the genus Ternidens（Strongyloidea: Chabertiidae） found in a talapoin, Miopithecus talapoin, imported for sale as a pet. (2019)
  • Author(s): Hasegawa H, Matsuura K and Asakawa M.
  • Journal Title: Jpn. J. Vet. Parasitol. Volume: 18(2) Pages: 65-71
  • NAID: 120006779132
  • Peer Reviewed
• [Presentation] 腎特異的SAV1ノックアウトマウスは、 VHL欠失とは異なる表現型を示す (2020)
  • Author(s): 松浦 恵子、吉田 知弘 、池田 八果穂 、 甲斐 友喜 、守山 正胤 、三股 浩光
  • Organizer: 第109回 日本病理学会総会