胃がん及び膵がんにおけるWNT信号伝達系の異常による転写標的遺伝子の同定

• Project/Area Number: 13218146
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas (C)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: National Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East
• Principal Investigator: 加藤 勝 国立がんセンター研究所, 分子腫瘍学部・細胞遺伝研究室, 室長 (50233820)
• Project Period (FY): 2001
• Project Status: Completed (Fiscal Year 2001)
• Budget Amount: ¥6,700,000 (Direct Cost: ¥6,700,000); Fiscal Year 2001: ¥6,700,000 (Direct Cost: ¥6,700,000)
• Keywords: WNT / beta-catenin / 胃がん / 膵がん / 腫瘍マーカー / 早期診断 / ゲノム科学 / 再生医療

Research Abstract

WNT-beta-catenin信号伝達系の正の制御因子のgain-of-function遺伝子変異及びWNT-beta-catenin信号伝達系の負の制御因子のloss-of-function遺伝子変異が種々のがんの発生進展に関与している。WNTシグナルは7回膜貫通型受容体を介して、beta-catenin-TCF信号伝達系、JNK信号伝達系、或いはCa^<2+>信号伝達系へと伝達される。膵がん細胞株においてWNT信号伝達系の活性化によりbeta-cateninが安定化される実験系を確立して、アレイ解析より新たなWNT信号伝達系転写標的遺伝子WPC-01,WPC-02の同定に成功した。また、バイオインフォマティクスを用いたゲノム概要配列の解析とcDNA-PCRなどにより、WNT信号伝達系関連遺伝子WNT3,WNT3A,WNT5B,WNT6,WNT7B,WNT8A,WNT8B,WNT10A,WNT10B,WNT11,WNT14,WNT14B/WNT15,FZD5,FZD8,MFRP,NKD1,NKD2,FRAT1,FRAT2,LZIC,SOX17,GIPC2,GIPC3,VANGL1/STB2,VANGL2/STB1,ARHU/WRCH1,ARHV/WRCH2,WINS1,WINS2の分離同定に成功した。更に原発胃がんにおける19種類のヒトWNT遺伝子の発現を解析して、WNT2,WNT2B,WNT5A,WNT10A,WNT16が比較的高頻度に発現上昇している事を発見した。WNT-beta-catenin信号伝達系の正の制御因子をコードするWNT2,WNT2B,WNT3,WNT3A,WNT8A,WNT8B,WNT10A,WNT10B,FRAT1,FRAT2はがん遺伝子の候補であり、WNT-beta-catenin信号伝達系の負の制御因子をコードするNKD1,NKD2,VANGL1,VANGL2はがん抑制遺伝子の候補であった。本研究の成果は、胃がん・膵がんなどの消化器がんに対する新たな診断法・予防法・治療法の開発に応用できると期待されれる。

Research Products

• [Publications] Spiegelman VS, Tang W, Katoh M et al.: "Inhibition of HOS expression and activities by WNT pathway"Oncogene. 21. 856-860 (2002)
• [Publications] Katoh M.: "Molecular cloning and characterization of ST7R(ST7-like, ST7L)on human chromosome 1p13, a novel gene homologous to tumor suppressor gene ST7 on human chromosome 7q31"Int. J. Oncol. 20. 1247-1253 (2002)
• [Publications] Katoh M.: "Strabismus(STB)/Vang-like(VANGL)gene family(Review)"Int. J. Mol. Med.. 10. 11-15 (2002)
• [Publications] Katoh M.: "Structure and expression of Strabismus 1 gene on human chromosome 1q21-q23"Int. J. Oncol.. 20. 1197-1203 (2002)
• [Publications] Katoh M.: "GIPC gene family(Review)"Int. J. Mol. Med.. 9. 585-589 (2002)
• [Publications] Katoh M.: "WNT3-WNT14B and WNT3A-WNT14 gene clusters(Review)"Int. J. Mol. Med.. 9. 579-584 (2002)
• [Publications] Saitoh T, Mine T, Katoh M.: "Frequent up-regulation of WNT5A mRNA in primary gastric cancer"Int. J. Mol. Med.. 9. 515-519 (2002)
• [Publications] Kirikoshi H, Katoh M.: "Expression of human GIPC1 in normal tissues, cancer cell lines, and primary tumors"Int. J. Mol. Med.. 9. 509-513 (2002)
• [Publications] Saitoh T, Mine T, Katoh M.: "Expression and regulation of WNT8A and WNT8B mRNAs in human tumor cell lines : up-regulation of WNT8B mRNA by-estradiol in MCF-7 cells, and down-regulation of WNT8A and WNT8B mRNAs by retinoic acid in NT2 ceIls"Int. J. Oncol. 20. 999-1003 (2002)
• [Publications] Katoh M.: "Molecular cloning and characterization of Strabismus2 (STB2)"Int. J. Oncol.. 20. 993-998 (2002)
• [Publications] Katoh M.: "Molecular cloning and characterization of WRCH2 on human chronmosome 15q15"Int. J. Oncol.. 20. 977-982 (2002)
• [Publications] Saitoh T, Mine T, Katoh M.: "Molecular cloning and expression of proto-oncogene FRAT1 in human cancer"Int. J. Oncol.. 20. 785-789 (2002)
• [Publications] Kirikoshi H, Katoh M.: "Expression of WRCH1 in human cancer and down-regulation of WRCH1 by B-estradiol in MCF-7 cells"Int. J. Oncol.. 20. 777-783 (2002)
• [Publications] Katoh M.: "Expression of human SOX7 in normal tissues and tumors"Int. J. Mol. Med.. 9. 363-368 (2002)
• [Publications] Saitoh T, Mine T, Katoh M.: "Molecular cloning and characterization of mouse Gipc3"Int. J. Mol. Med.. 9. 251-256 (2002)
• [Publications] Katoh M.: "Molecular cloning and expression of mouse Wnt14, and structural comparison between mouse Wnt14-Wnt3a gene cluster and human WNT14-WNT3A gene cluster"Int. J. Mol. Med.. 9. 221-227 (2002)
• [Publications] Saitoh T, Mine T, Katoh M.: "Molecular cloning and characterization of human GIPC3, a novel gene homologous to human GIPC1 and GIPC2"Int. J. Oncol.. 20. 577-582 (2002)
• [Publications] Kirikoshi H, Katoh M.: "Molecular cloning and characterization of human GIPC2, a novel gene homologous to human GIPC1 and Xenopus Kermit"Int. J. Oncol.. 20. 571-576 (2002)
• [Publications] Katoh M.: "Regulation of WNT3 and WNT3A mRNAs in human cancer cell lines NT2, MCF-7, and MKN45"Int. J. Oncol.. 20. 373-377 (2002)
• [Publications] Saitoh T, Mine T, Katoh M.: "Up-regulation of WNT8B mRNA in human gastric cancer"Int. J. Oncol.. 20. 343-348 (2002)
• [Publications] Katoh M.: "Molecular cloning and characterization of human SOX 17"Int. J. Mol. Med.. 9. 153-157 (2002)
• [Publications] Kirikoshi H, Katoh M.: "Molecular cloning and characterization of mouse Wnt14b, clustered with mouse Wnt3 in mouse chromosome 11"Int. J. Mol. Med.. 9. 135-139 (2002)
• [Publications] Saitoh T, Mine T, Katoh M.: "Up-regulation of Frizzled-10(FZD10) by β-estradiol in MCF-7 ce11s and by retinoic acid in NT2 cells"Int. J. Oncol.. 20. 117-120 (2002)
• [Publications] Terasaki H, Saitoh T, Shiokawa K, Katoh M.: "Frizzled-10, up-regulated in primary colorectal cancer, is a positive regulator of the WNT-β-catenin-TCF signaling pathway"Int. J. Mol. Med.. 9. 107-112 (2002)
• [Publications] Katoh M et al.: "WNT2B2 mRNA, up-regulated in primary gastric cancer, is a positive regulator of the WNT-beta-catenin-TCF signaling pathweay"Biochem. Biophys. Res. Commun.. 289. 1093-1098 (2001)
• [Publications] Kirikoshi H, Sekihara H, Katoh M.: "Expression of WNT14 and WNT14B mRNAs in human cancer, up-regulation of WNT14 by IFNγ and up-regulation of WNT14B byβ-estradiol"Int. J. Oncol.. 19. 1221-1225 (2001)
• [Publications] Saitoh T, Kirikoshi H, Mine T, Katoh M.: "Proto-oncogene WNT10B is up-regulated by tumor necrosis factor α in human gastric cancer cell line MKN45"Int. J. Oncol.. 19. 1187-1192 (2001)
• [Publications] Katoh M.: "Differential regulation of WNT2 and WNT2B expression in human cancer"Int. J. Mol. Med.. 8. 657-660 (2001)
• [Publications] Kirikoshi H, Sekihara H, Katoh M.: "Molecular cloning and characterization of human WNT11"Int. J. Mol. Med.. 8. 651-656 (2001)
• [Publications] Katoh M.: "Molecular cloning and characterization of LZIC, a novel gene encoding ICAT homologous protein with leucine zipper domain"Int. J. Mol. Med.. 8. 611-615 (2001)
• [Publications] Katoh M.: "Frequent up-regulation of WNT2 in primary gastric cancer and colorectal cancer"Int. J. Oncol.. 19. 1003-1007 (2001)
• [Publications] Kirikoshi H, Inoue S, Sekihara H, Katoh M.: "Expression of WNT10A in human cancer"Int. J. Oncol. 19. 997-1001 (2001)
• [Publications] Katoh M.: "Molecular cloning and characterization of human WNT3"Int. J. Oncol.. 19. 977-982 (2001)
• [Publications] Katoh M.: "Molecular cloning, gene structure, and expression analyses of NKD1 and NKD2"Int. J. Oncol.. 19. 963-969 (2001)
• [Publications] Kirikoshi H, Sekihara H, Katoh M.: "Molecular cloning and characterization of WNT14B, a novel member of the WNT gene family"Int. J. Oncol.. 19. 947-952 (2001)
• [Publications] Kirikoshi H, Sekihara H, Katoh M.: "Molecular cloning and characterization of human WNT7B"Int. J. Oncol.. 19. 779-783 (2001)
• [Publications] Kirikoshi H, Sekihara H, Katoh M.: "Expression profile of 10 members of Frizzled gene family in human gastric cancer"Int, J. Oncol.. 19. 767-771 (2001)
• [Publications] Kirikoshi H, Sekihara H, Katoh M.: "Up-regulation of WNT10A by tumor necrosis factor alpha and Helicobacter pylori in gastric cancer"Int. J. Oncol.. 19. 533-536 (2001)
• [Publications] Saitoh T, Katoh M.: "Molecular cloning and characterization of human WNT5B on chromosome 12p13.3 region"Int. J. Oncol.. 19. 347-351 (2001)
• [Publications] Saitoh T, Katoh M.: "FRAT1 and FRAT2, clustered in human chromosome 10q24.1 region, are up-regulated in gastric cancer"Int. J. Oncol.. 19. 311-315 (2001)
• [Publications] Saitoh T, Hirai M, Katoh M.: "Molecular cloning and characterization of WNT3A and WNT14 clustered in human chromosome 1q42 region"Biochem. Biophys. Res. Commun.. 284. 1168-1175 (2001)
• [Publications] Saitoh T, Katoh M.: "Molecular cloning and characterization of human WNT8A"Int. J. Oncol.. 19. 123-127 (2001)
• [Publications] Kirikoshi H, Sekihara H, Katoh M.: "Up-regulation of Frizzled-7(FZD7)in human gastric cancer"Int. J. Oncol.. 19. 111-115 (2001)
• [Publications] Kirikoshi H, Sekihara H, Katoh M.: "WNT10A and WNT6,clustered in human chromosome 2q35 region with head-to-tail manner, are strongly coexpressed in SW480 cells"Biochem. Biophys. Res. Commun.. 283. 798-805 (2001)
• [Publications] Saitoh T, Hirai M, Katoh M.: "Molecular cloning and characterization of human Frizzled-5 gene on chromosome 2q33.3-q34 region"Int. J. Oncol.. 19. 105-110 (2001)
• [Publications] Katoh M.: "Molecular cloning and characterization of RNF26 on human chromosome 11q23 region, encoding a novel RING finger protein with leucine zipper"Biochem. Biophys. Res. Commun.. 282. 1038-1044 (2001)
• [Publications] Sagara N, Kirikoshi H, Terasaki H, Yasuhiko Y, Toda G, Shiokawa K, Katoh M.: "FZD4S, a splicing variant of Frzzled-4, encodes a soluble-type positive regulator of the WNT signaling pathway"Biochem. Biophys. Res. Commun.. 282. 750-756 (2001)
• [Publications] Saitoh T, Hirai M, Katoh M.: "Molecular cloning and characterization of human Frizzled-8 gene on chromosome 10p11.2"Int. J. Oncol.. 18. 991-996 (2001)
• [Publications] Saitoh T, Katoh M.: "Expression profiles of BTRCP1 and BTRCP2, and mutation analysis of BTRCP2 in gastric cancer"Int. J. Oncol.. 18. 959-964 (2001)
• [Publications] Katoh M.: "Molecular cloning and characterization of MFRP, a novel gene encoding Frizzled-related protein"Biochem. Biophys. Res. Commun.. 282. 116-123 (2001)
• [Publications] Saitoh T, Moriwaki J, Koike J, Takagi A, Miwa T, Shiokawa K, Katoh M.: "Molecular cloning and characterization of FRAT2, encoding a positive regulator of the WNT signaling pathway"Biochem. Biophys. Res. Commun.. 281. 815-820 (2001)