Identification of novel imprinted tumor suppressor gene on 14q for human renal mil carcinoma

• Project/Area Number: 17390438
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Urology
• Research Institution: Shiga University of Medical Science
• Principal Investigator: KAWAKAMI Takahiro Shiga University of Medical Science, School of Medicine, Assistant Professor (90346023)
• Co-Investigator(Kenkyū-buntansha): OKAMOTO Keisei Shiga University of Medical Science, School of Medicine, Assistant Professor (50303780) ; OKADA Yusaku Shiga University of Medical Science, School of Medicine, Professor (20127062) ; NARITA Mitsuhiro Shiga University of Medical Science, School of Medicine, Assistant Professor (00263046) ; JOHNIN Kazuyicshi Shiga University of Medical Science, School of Medicine, Assistant Professor (90324590) ; USHIDA Hiroshi Shiga University of Medical Science, School of Medicine, Assistant Professor (80418756) ; 坂野 祐司 滋賀医科大学, 医学部, 助手 (00346016)
• Project Period (FY): 2005 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥16,750,000 (Direct Cost: ¥15,400,000、Indirect Cost: ¥1,350,000); Fiscal Year 2007: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2006: ¥5,900,000 (Direct Cost: ¥5,900,000); Fiscal Year 2005: ¥5,000,000 (Direct Cost: ¥5,000,000)
• Keywords: Renal cell carcinoma / DLK1 / Imorintine gene / インプリンティング

Research Abstract

A common deletion at chromosomal arm 14q32 in human renal cell carcinoma (RCC) prompted us to explore a tumor suppressor gene (TSG) in this region. We report that imprinted DLK1 at 14q32, a regulator of adipocyte differentiation, is a candidate TSG in RCCs. Expression of DLK1 were diminished in both early and advanced stages of RCCs while normal kidney tissues expressed DLKI. Reintroduction of DLKI into DLK1-null RCC cell lines markedly increased anchorage-independent cell death, anoikis, and suppressed tumor growth in nude mice. Furthermore, we show that gain of methylation upstream of GTL2, a reciprocal imprinted gene for DLK1, is a critical epigenetic alteration for the inactivation of DLK1 in RCCs. The imprinted DLKI/GTL2 domain at 14q32 shares structural and epigenetic similarities with the IGF2/H19 domain at 11p15.5. Gain of methylation upstream of the untranslated H19 leads to pathological biallelic expression of IGF2 in Wilms tumors. In contrast, the present data have shown that gain of methylation upstream of the untranslated GTL2 leads to pathological down regulation of DLK1 in RCCs.

Research Products

• [Journal Article] Epigenetic profile of testicular germ cell tumours. (2007)
  • Author(s): Okamoto, K. and Kawakami, T.
  • Journal Title: lnt J Androl 30 Pages: 385-392
  • Peer Reviewed
• [Journal Article] GADD34 induces p21 expression and cellular senescence (2007)
  • Author(s): Minami, K., Inoue, H., Terashita, T., Kawakami, T., et. al.
  • Journal Title: Oncol Rep 17 Pages: 1481-1485
  • Peer Reviewed
• [Journal Article] Imprinted DLK1 is a putative tumor suppressor gene and inactivated by epimutation at the region upstream of GTL2 in human renal cell carcinoma (2006)
  • Author(s): Kawakami, T., Chano, T., Minami, K., Okabe, H., Okada, Y. and Okamoto, K
  • Journal Title: Human Molecular Genetics 15 Pages: 821-830
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Imprinted DLK1 is a putative tumor suppressor gene and inactivated by epimutation at the region upstream of GTL2 in human renal cell carcinoma (2006)
  • Author(s): Kawakami, T., Chano, T., Minami, K., Okabe, H., Okada, Y., Okamoto, K
  • Journal Title: Human Molecular Genetics 15 Pages: 821-830
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Distinctive epigenetic phenotype of cancer testis antigen genes among seminomatous and nonseminomatous testicular germ-cell tumors (2005)
  • Author(s): Zhang, C., Kawakami, T., Okada, Y., Okamoto, K.
  • Journal Title: Genes Chromosomes Cancer 43 Pages: 104-112