Prevention of renal cell carcinoma in acquired renal cystic disease through inhibition of HGF/c-met signaling pathway

• Project/Area Number: 16591615
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Urology
• Research Institution: Iwate Medical University
• Principal Investigator: KONDA Ryuichiro Iwate Medical university, School of Medicine, Associate Prof., 医学部, 助教授 (10225609)
• Co-Investigator(Kenkyū-buntansha): OBARA Wataru Iwate Medical University, School of Medicine, Assistant, 医学部, 助手 (90337155)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000); Fiscal Year 2004: ¥2,100,000 (Direct Cost: ¥2,100,000)
• Keywords: renal failure / renal cyst / renal cell carcinoma / hepatocyte growth factor / c-met / Akt / PTEN / p27 / hepatocyte growth factor / IGFR-1 / 後天性嚢胞腎 / 胚不全増殖因子 / C-met / P27

Research Abstract

The development of renal cell carcinoma (RCC) is a critical problem of acquired renal cystic disease (ARCD) in patients with end-stage renal disease (ESRD). We examined the expression of hepatcyte growth factor (HGF) and its receptor c-met in ARCD associated with RCC to elucidate the role of HGF/c-met pathway in renal cyst development and subsequent tumor transformation. C-metimmunostaining was observed mainly in the distal tubular cells. In non-tumor areas of kidneys with ARCD-associated RCC, expression of HGF and c-met was up-regulated in the tubular and the cyst epithelial cells. Hyperplastic cysts with multilayer epithelium and micropapillary projection were the predominant cysts stained with HGF and c-met. Immunostaining for HGF and c-met was also detected in the RCC regions. Since HGF activated the antiapoptotic factor Akt and the cytoprotective action of HGF is dependent, in part, upon Akt, we examined the expression of activated Akt (pAkt) in ARCD associated with RCC. Moreover, expressions of the Akt activation inhibitor PTEN and the cyclin dependent kinase inhibitor p27 were examined. In non-tumor areas of kidneys with ARCD-associated RCC, expression of pAkt, PTEN and p27 was up-regulated in the tubular cells including dilated tubules. pAkt and PTEN immunostaining was predominantly observed in cuboidal and hyeprplastic epithelial cyts but not in flat cysts as HGF and c-met immunostaining. In contrast, expression of p27 was scarcely observed in the cyst epithelial cells. Immunostaining for pAkt, PTEN and p27 was also detected in the RCC regions though expression of p27 was lower in these regions than in tubular cells. These results suggest that HGF and its receptor c-met may be involved in renal cyst formation and subsequent tumor transformation in patients with ESRD via up-regulation of PI3-kinase/Akt pathway. Decreased expression of p27 may promote this process.

Research Products

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  • Author(s): Obara W, Konda R, Seo T, Ishikawa K, Kinjo M, Fujioka T
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• [Journal Article] Perinephric angiomyolipoma : A unique development pattern surrounding the kidney (2005)
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  • Journal Title: Int.J.Urol 12 Pages: 305-307
  • NAID: 10015525367
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] C-kit expression in renal oncocytomas and chromophobe renal cell caricnoma (2005)
  • Author(s): Lei H, Sugimura J, Maria S.T, Kurt T.P, Pohit G, Boris P, William B, Laskin MD, Anjana Y MD, Bin T.T, Ximing J.Y MD, phD
  • Journal Title: Human Pathology 36 Pages: 262-268
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Overexpression of Glutathione S-Transferase α in Clear Renal Cell Carcinoma (2005)
  • Author(s): Shang-Tian C, DO, Peiguo C, MD, PhD, Sugimura J, MD, Maria S.T, MD, Veronica P, MD, Kim W, MD, MinHan T, MD, FanLin, MD, PhD, Bin T.T, MD, PhD, Ximing J.Y,MD,PhD
  • Journal Title: Am J Clin Pathology 123 Pages: 421-429
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Association of a single-nucleotide polymorphism in the immunoglobulin ц-binding protein 2 gene with immunoglobulin A nephropathy (2005)
  • Author(s): Ohtsubo S, Iida A, Nitta K, Tanaka T, Yamada R, Ohnishi Y, Maeda S, Tsunoda T, Takei T, Obara W, Akiyama F, Ito K, Honda K, Uchida K, Tsuchiya K, Yumura W, Ujiie T, Nagane Y, Miyano S, Suzuki Y, Narita I, Gojyo F, Fujioka T, Nihei H, Nakamura Y
  • Journal Title: J Hum Genet 50 Pages: 30-35
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Perinephric angiomyolipoma : A unique development pattern surrounding the kidney (2005)
  • Author(s): Obara W, Sato K, Owari Y, Nozawa T, Isurugi, K, Ohmori S, Mastushita Y, Tanji S, Konda R, Fujioka T
  • Journal Title: Int.J.Urol 12 Pages: 305-307
  • NAID: 10015525367
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] C-kit expression in renal oncocytomas and chromophobe renal cell caricnoma (2005)
  • Author(s): Lei H, Sugimura J, Maria S.T, Kurt T.P, Pohit G, Boris P, William B, Laskin MD., Anjana Y MD., Bin T.T, Ximing J.Y MD., phD.
  • Journal Title: Human Pathology 36 Pages: 262-268
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Overexpression of Glutathione S-Transferase α in Clear Renal Cell Carcinoma (2005)
  • Author(s): Shang-Tian C, DO, Peiguo C, MD., PhD, Sugimura J, MD., Maria S.T, MD., Veronica P, MD., Kim W, MD., MinHan T, MD., Fan Lin, MD., PhD., Bin T.T, MD., PhD., Ximing J.Y, MD., PhD.
  • Journal Title: Am J Clin Pathology 123 Pages: 421-429
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Association of a single-nucleotide polymorphism in the immunoglobulin u-binding protein 2 gene with immunoglobulin A nephropathy (2005)
  • Author(s): Ohtsubo S, Iida A, Nitta K, Tanaka T, Yamada R, Ohnishi Y, Maeda S, Tsunoda T, Takei T, Obara W, Akiyama F, Ito K, Honda K, Uchida K, Tsuchiya K, Yumura W, Ujiie T, Nagane Y, Miyano S, Suzuki Y, Narita I, Gojyo F, Fujioka T, Nihei H, Nakamura Y
  • Journal Title: J Hum Gene 50 Pages: 30-35
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cardiovascular risk factor in hemodialysis patients : Results from baseline data of kaleidoscopic approaches to patients with end-stage renal disease study (2005)
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  • Journal Title: J Epidemiol 15 Pages: 96-105
  • NAID: 10015648862
• [Journal Article] Perinephric angiomyolipoma : a unique development pattern surrounding the kidney (2005)
  • Author(s): Obara W, Sato K, Oawari Y, Nozawa T, Isurugi K, Ohmori S, Matsushita Y, Tanji S, Konda R, Fujioka T
  • Journal Title: Int J Urol 12 Pages: 305-307
  • NAID: 10015525367
• [Journal Article] Expression of hepatocyte growth factor and its receptor C-MET in acquired renal cystic disease associated with renal cell carcinoma (2004)
  • Author(s): Konda R, Sato H, Hatafuku F, Nozawa T, Fujioka T
  • Journal Title: J.Urol 171 Pages: 2166-2170
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Robust Classification of Renal Cell Carcinoma Based on Gene Expression Data and Predicted Cytogenetic Profiles (2004)
  • Author(s): Kyle A.F, Kerry A.L, Takahashi M, Sugimura J, Eric J.K, Kanayama H, Kagawa S, Philip H, John C, Ximing J.Y, Bin T.T
  • Journal Title: Cancer Res 64 Pages: 4117-4121
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Gene Expression Profiling of Early- and Late-Relapse Nonseminomatous Germ Cell Tumor and Primitive Neuroectodermal Tumor of the Testis (2004)
  • Author(s): Sugimura J, Richard S.F, Oscar W.C, Eric J.K, Takahashi M, Todd T.L, Kyle A.F, Lawrence H.E, Bin T.T
  • Journal Title: Clinical Cancer Research 10 Pages: 2368-2378
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Gene Expression Profiling of Renal Medullary Carcinoma (2004)
  • Author(s): Ximing J.Y, Sugimura J, Maria S.T, Kyle F, Gregory Z, Michell S, Michel P, Raymond B, David J.G, Wlter M.S, Nicholas J.V, Bin T.T
  • Journal Title: Cancer 100 Pages: 976-985
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Expression of hepatocyte growth factor and its receptor C-MET in acquired renal cystic disease associated with renal cell carcinoma (2004)
  • Author(s): Konda R, Hatafuku F, Nozawa T, Fujioka T
  • Journal Title: J.Urol 171 Pages: 2166-2170
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Robust Classification of Renal Cell Carcinoma Based on Gene Expression Data and Predicted Cytogenetic Profiles (2004)
  • Author(s): Kyle A.F, Kerry A.L, Takahashi M, Sugimura J, Eric J.K, Kanayama H, Kagawa S, Philip H, John C, Ximing J.Y, Bin T.T
  • Journal Title: Cancer Res. 64 Pages: 4117-4121
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression of growth factor and its receptor C-met in acquired renal cystic disease associated with renal cell carcinoma (2004)
  • Author(s): Ryuichiro Konda
  • Journal Title: J Urol 171 Pages: 2166-2170