Analysis of roles of alterations in non-coding region of genes in carcinogenesis with microsatellite instability

• Project/Area Number: 16390213
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Sapporo Medical University
• Principal Investigator: YAMAMOTO Hiroyuki Sapporo Medical University, School of Medicine, Instructor, 医学部, 助手 (40332910)
• Co-Investigator(Kenkyū-buntansha): ADACHI Masaaki Sapporo Medical University, School of Medicine, Associate Professor, 医学部, 助教授 (70240926)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥13,700,000 (Direct Cost: ¥13,700,000); Fiscal Year 2005: ¥5,600,000 (Direct Cost: ¥5,600,000); Fiscal Year 2004: ¥8,100,000 (Direct Cost: ¥8,100,000)
• Keywords: DNA mismatch repair gene / microsatellite instability / non-coding region / 5'-UTR / 3'-UTR / 遺伝子発現

Research Abstract

We have identified cancer-related genes of which expressions are regulated by microsatellite length in non-coding region. We have also revealed the effects of microsatellite length alterations on the expression of these genes by in vitro and in vivo experiments. Frequency of mutations of these genes was shown in MSI-positive gastrointestinal cancer tissues and cell lines. Several subclones with different microsatellite length in particular genes were developed. Correlation of microsatellite length with gene expression was shown in these subclones and MSI-positive gastrointestinal cancer tissues and cell lines.
The expression of target genes of which mononucleotide repeats were located in 5'-UTR was often downregulated in MSI-positive cancers. MSI could be responsible for the decreased transcript levels of genes containing 5'-UTR microsatellites. Alterations in the 5'-UTR could diminish transcription efficiency. Thus, this appears one of the mechanisms underlying the inactivation of tumor suppressor genes. On the other hand, the expression of target genes of which mononucleotide repeats were located in 3'-UTR was often upregulated in MSI-positive cancers. Moreover, the repeat length was often shortened in cancer. This seems one of the mechanisms underlying activation of oncogenes. We have also revealed that poly(U)-tract length could affect RNA stability and processing and translation efficiency.
These results suggest that microsatellite length alterations in non-coding region of cancer-related genes play an important role in the development and progression of MSI-positive gastrointestinal cancers.

Research Products

• [Journal Article] A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition (2006)
  • Author(s): Santiago Ropero
  • Journal Title: Nat Genet 41 Pages: 566-569
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition. (2006)
  • Author(s): Ropero, S., Fraga, M., Ballestar, E., Hamelin, R., Yamamoto, H., Boix-Chornet, M., Caballero, R., Alaminos, M., Setien, F., Paz, M.F., Herranz, M., Palacios, J., Arango, D., Orntoft, T.F., Aaltonen, L.A., Schwartz, S.Jr., Esteller, M.
  • Journal Title: Nat.Genet. 41 Pages: 566-569
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] BRAF-V600E is not involved in the colorectal tumorigenesis of HNPCC patients with functional MLH1 and MSH2 genes (2005)
  • Author(s): Enric Domingo
  • Journal Title: Oncogene 24 Pages: 3995-3998
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Concomitant RASSF1A hypermethylation and KRAS/BRAF mutations occur preferentially in MSI sporadic colorectal cancer (2005)
  • Author(s): Carla Oliveira
  • Journal Title: Oncogene 25 Pages: 7630-7634
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Mechanisms of inactivation of the receptor tyrosine kinase EPHB2 in colorectal tumors (2005)
  • Author(s): Hafid Alazzouzi
  • Journal Title: Cancer Res 65 Pages: 10170-10713
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Frequent epigenetic inactivation of Wnt inhibitory factor-1 in human gastrointestinal cancers (2005)
  • Author(s): Hiroaki Taniguchi
  • Journal Title: Oncogene 24 Pages: 7946-7952
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] BRAF-V600E is not involved in the colorectal tumorigenesis of HNPCC patients with functional MLH1 and MSH2 genes. (2005)
  • Author(s): Domingo, E., Niessen, R.C., Oliveira, C., Alhopuro, P., Moutinho, C., Espin, E., Armengol, M., Sijmons, R.H., Kleibeuker, J.H., Seruca, R., Aaltonen, L.A., Imai, K., Yamamoto, H., Schwartz, S.Jr., Hofstra, R.M.W.
  • Journal Title: Oncogene 24 Pages: 3995-3998
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Concomitant RASSF1A hypermethylation and KRAS/BRAF mutations occur preferentially in MSI sporadic colorectal cancer. (2005)
  • Author(s): Oliveira, C., Velho, S., Domingo, E., Preto, A., Hofstra, R.M.W., Hamelin, R., Yamamoto, H., Seruca, R., Schwartz, S.Jr.
  • Journal Title: Cancer Res. 65 Pages: 10170-10173
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Mechanisms of inactivation of the receptor tyrosine kinase EPHB2 in colorectal tumors. (2005)
  • Author(s): Alazzouzi, H., Davalos, V., Kokko, A., Domingo, E., Woerner, S.M., Wilson, A.J., Imai, K., Yamamoto, H., Mariadason, J.M., Gebert, J.F., Aaltonen, L.A., Simo Schwartz, S.Jr., Arango, D.
  • Journal Title: Oncogene 24 Pages: 7630-7634
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Frequent epigenetic inactivation of Wnt inhibitory factor-1 in human gastrointestinal cancers. (2005)
  • Author(s): Taniguchi, H., Yamamoto, H.(co-first), Hirata, T., Miyamoto, M., Oki, M., Nosho, K., Imsumran, A., Adachi, Y., Endo, T., Imai, K., Shinomura, Y.
  • Journal Title: Oncogene 24 Pages: 7946-7952
  • NAID: 130004927581
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Concomitant RASSFIA hypermethylation and KRAS/BRAF mutations occur preferentially in MSI sporadic colorectal cancer (2005)
  • Author(s): Carla Oliveira
  • Journal Title: Oncogene 25 Pages: 7630-7634
• [Journal Article] Mechanisms of inactivation of the receptor tyrosine kinase EPHB2 in colorectal tumors (2005)
  • Author(s): Hafid Alazzouzi
  • Journal Title: Cancer Research 65 Pages: 10170-10713
• [Journal Article] BRAF-V600E is not involved in the colorectal tumorigenesis of HNPCC patients with functional MLH1 and MSH2 genes (2005)
  • Author(s): Enric Domingo
  • Journal Title: Oncogene 24(in press)
• [Journal Article] Activated BRAF targets proximal colon tumors with mismatch repair deficiency and hMLH1 inactivation (2004)
  • Author(s): Enric Domingo
  • Journal Title: Genes Chromosomes Cancer 39 Pages: 138-142
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Braf screening as a low-cost effective strategy for simplifying HNPCC genetic testing (2004)
  • Author(s): Enric Domingo
  • Journal Title: J Med Genet 41 Pages: 663-667
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Distinct patterns of KRAS mutations in colorectal carcinomas according to germline mismatch repair defects and hMLH1 methylation status (2004)
  • Author(s): Carla Oliveira
  • Journal Title: Hum Mol Genet 13 Pages: 2303-2311
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Activated BRAF targets proximal colon tumors with mismatch repair deficiency and MLH1 inactivation. (2004)
  • Author(s): Domingo, E., Espin, E., Armengol, M., Oliveira, C., Pinto, M., Duval, A., Brennetot, C., Seruca, R., Hamelin, R., Yamamoto, H., Schwartz, S.Jr.
  • Journal Title: Genes Chromosomes Cancer 39 Pages: 138-142
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Braf screening as a low-cost effective strategy for simplifying HNPCC genetic testing. (2004)
  • Author(s): Domingo, E., Laiho, P., Ollikainen, M., Pinto, M., Wang, L., French, A.J., Westra, J., Frebourg, T., Espin, E., Armengol, M., Hamelin, R., Yamamoto, H., Hofstra, R.M.W., Seruca, R., Lindblom, A., Peltomaki, P., Thibodeau, S.N., Aaltonen, L.A., Schwartz, S.Jr.
  • Journal Title: J Med.Genet. 41 Pages: 663-667
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Distinct patterns of KRAS mutations in colorectal carcinomas according to germline mismatch repair defects and hMLH1 methylation status. (2004)
  • Author(s): Oliveira, C., Westra, J.L., Arango, D., Ollikainen, M., Domingo, E., Ferreira, A., Velho, S., Niessen, R., Lagerstedt, K., Alhopuro, P., Laiho, P., Veiga, I., Teixeira, M.R., Ligtenberg, M., Kleibeuker, J.H., Sijmons, R.H., Plukker, J.T., Imai, K., Lage, P., Hamelin, R., Albuquerque, C., Schwartz, S.Jr., Lindblom, A., Peltomaki, P., Yamamoto, H., Aaltonen, L.A., Seruca, R., Hofstra, R.M.
  • Journal Title: Hum.Mol.Genet. 13 Pages: 2303-2311
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression of ets-related transcriptional factor E1AF is associated with tumor progression and overexpression of matrilysin in human gastric cancer (2004)
  • Author(s): Hiroyuki Yamamoto
  • Journal Title: Carcinogenesis 25 Pages: 325-332
• [Journal Article] Interplay of IGF-II, IGF-I, IGF-I receptor, COX-2, and MMP-7 plays Key roles in the early stage of colorectal carcinogenesis (2004)
  • Author(s): Katsuhiko Nosho
  • Journal Title: Clin Cancer Res 10 Pages: 7950-7957