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. 2005 Aug 19;94(8):712–717. doi: 10.1111/j.1349-7006.2003.tb01507.x

Overexpression of the Wilms' tumor gene WT1 in colorectal adenocarcinoma

Yusuke Oji 1, Hirofumi Yamamoto 2, Masaya Nomura 3, Yoko Nakano 1, Ai Ikeba 1, Shin‐ichi Nakatsuka 4, Sakie Abeno 1, Eiji Kiyotoh 1, Tanyarat Jomgeow 1, Mitsugu Sekimoto 2, Riichiro Nezu 5, Yukinobu Yoshikawa 3, Yoshifumi Inoue 3, Naoki Hosen 6, Manabu Kawakami 7, Akihiro Tsuboi 7, Yoshihiro Oka 6, Hiroyasu Ogawa 6, Shigeo Souda 3, Katsuyuki Aozasa 4, Morito Monden 2, Haruo Sugiyama 1,7,
PMCID: PMC11160268  PMID: 12901797

Abstract

Expression of the Wilms' tumor gene WT1 was examined in 59 cases of colorectal adenocarcinoma to examine the involvement of WT1 in tumorigenesis. Quantitative real‐time reverse transcription‐polymerase chain reaction (RT‐PCR) showed that WT1 mRNA was expressed in the range from 7.2x10−5 to 4.9x10−1 levels (WT1 expression level in K562 leukemic cells was defined as 1.0) in all (100%) of the 28 cases of colorectal adenocarcinoma examined, and that the WT1 mRNA expression levels were higher in 20 (71%) of the 28 cases compared to those of normal‐appearing mucosal tissues examined. Immunohistochemical analysis using an anti‐WT1 antibody was performed on 46 cases of colorectal adenocarcinoma (15 of the 28 cases with WT1 mRNA expression and 31 newly collected cases), and the expression of WT1 protein was detected in 41 (89%) of the 46 cases. The direct sequencing analysis of the WT1 genomic DNA showed no mutations in any of the 10 exons of the WT1 gene in any of 5 different colorectal ade‐nocarcinomas. These results may indicate an important role of the wild‐type WT1 gene in tumorigenesis of colorectal adenocarcinoma.

References

  • 1. Call KM, Glaser TM, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH, Jones C, Housman DE. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell 1990; 60: 509–20. [DOI] [PubMed] [Google Scholar]
  • 2. Gessler M, Poustka A, Cavenee W, Neve RL, Orkin SH, Bruns GAP. Homozygous deletions in Wilms' tumours of a zinc‐finger gene identified by chromosome jumping. Nature 1990; 343: 7748. [DOI] [PubMed] [Google Scholar]
  • 3. Pelletier J, Bruening W, Li FP, Haber DA, Glaser T, Housman DE. WT1 mutations contribute to abnormal genital system development and hereditary Wilms' tumour. Nature 1991; 353: 431–4. [DOI] [PubMed] [Google Scholar]
  • 4. Gashler AL, Bonthron DT, Madden SL, Rauscher FJ 3rd, Collins T, Sukhatme VP. Human platelet derived growth factor A chain is transcription‐ally repressed by the Wilms tumor suppressor WT1. Proc Natl Acad Sci USA 1992; 89: 10984–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Harrington MA, Harrington MA, Konicek B, Song A, Xia XL, Fredericks WJ, Rauscher FJ 3rd. Inhibition of colony‐stimulating factor‐1 promoter activity by the product of the Wilms' tumor locus. J Biol Chem 1993; 268: 21271–5. [PubMed] [Google Scholar]
  • 6. Drummond IA, Madden SL, Rohwer‐Nutter P, Bell GI, Sukhatme VP, Rauscher FJ 3rd. Repression of the insulin‐like growth factor II gene by the Wilms tumor suppressor WT1. Science 1992; 257: 674–8. [DOI] [PubMed] [Google Scholar]
  • 7. Werner H, Re GG, Drummond IA, Sukhatme VP, Rauscher FJ 3rd, Sens DA, Garvin AJ, LeRoith D, Roberts CT Jr. Increased expression of the insulin‐like growth factor I receptor gene, IGFIR, in Wilms tumor is correlated with modulation of IGFIR promoter activity by the WT1 Wilms tumor gene product. Proc Natl Acad Sci USA 1993; 90: 5828–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Goodyer P, Dehbi M, Torban E, Bruening W, Pelletier J. Repression of the retinoic acid receptor‐alpha gene by the Wilms' tumor suppressor gene product, wt1. Oncogene 1995; 10: 1125–9. [PubMed] [Google Scholar]
  • 9. Hewitt SM, Hamada S, McDonnell TJ, Rauscher FJ 3rd, Saunders GF. Regulation of the proto‐oncogenes bcl‐2 and c‐myc by the Wilms' tumor suppressor gene WT1. Cancer Res 1995; 55: 5386–9. [PubMed] [Google Scholar]
  • 10. Oji Y, Ogawa H, Tamaki H, Oka Y, Tsuboi A, Kim EH, Soma T, Tatekawa T, Kawakami M, Asada M, Kishimoto T, Sugiyama H. Expression of the Wilms' tumor gene WT1 in solid tumors and its involvement in tumor cell growth. Jpn J Cancer Res 1999; 90: 194–204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Miwa H, Beran M, Saunders GF. Expression of the Wilms' tumor gene (WT1) in human leukemias. Leukemia 1992; 6: 405–9. [PubMed] [Google Scholar]
  • 12. Inoue K, Sugiyama H, Ogawa H, Nakagawa M, Yamagami T, Miwa H, Kita K, Hiraoka A, Masaoka T, Nasu K, Kyo T, Dohy H, Nakauchi H, Ishidate T, Akiyama T, Kishimoto T. WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia. Blood 1994; 84: 3071–9. [PubMed] [Google Scholar]
  • 13. Loeb DM, Evron E, Patel CB, Sharma PM, Niranjan B, Buluwela L, Weitzman SA, Korz D, Sukumar S. Wilms' tumor suppressor gene (WT1) is expressed in primary breast tumors despite tumor‐specific promoter methyla‐tion. Cancer Res 2001; 61: 921–5. [PubMed] [Google Scholar]
  • 14. Miyoshi Y, Ando A, Egawa C, Taguchi T, Tamaki Y, Tamaki H, Sugiyama H, Noguchi S. High expression of Wilms' tumor suppressor gene predicts poor prognosis in breast cancer patients. Clin Cancer Res 2002; 8: 1167–71. [PubMed] [Google Scholar]
  • 15. Oji Y, Miyoshi S, Maeda H, Hayashi S, Tamaki H, Nakatsuka S, Yao M, Takahashi E, Nakano Y, Hirabayashi H, Shintani Y, Oka Y, Tsuboi A, Hosen N, Asada M, Fujioka T, Murakami M, Kanato K, Motomura M, Kim EH, Kawakami M, Ikegame K, Ogawa H, Aozasa K, Kawase I, Sugiyama H. Overexpression of the Wilms' tumor gene WT1 in de novo lung cancers. Int J Cancer 2002; 100: 297–303. [DOI] [PubMed] [Google Scholar]
  • 16. Ueda T, Oji Y, Naka N, Nakano Y, Takahashi E, Koga S, Asada M, Ikeba A, Nakatsuka S, Abeno S, Hosen N, Tomita Y, Aozasa K, Tamai N, Myoui A, Yoshikawa H, Sugiyama H. Overexpression of the Wilms' tumor gene WT1 in human bone and soft‐tissue sarcomas. Cancer Sci 2003; 3: 271–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Oji Y, Inohara H, Nakazawa M, Nakano Y, Akahani S, Nakatsuka S, Koga S, Ikeba A, Abeno S, Honjo Y, Yamamoto Y, Iwai S, Yoshida K, Oka Y, Ogawa H, Yoshida Y, Aozasa K, Kubo T, Sugiyama H. Overexpression of the Wilms' tumor gene WT1 in head and neck squamous cell carcinoma. Cancer Sci 2003; 6: 523–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Yamagami T, Sugiyama H, Inuoe K, Ogawa H, Tatekawa T, Hirata M, Kudoh T, Akiyama T, Murakami A, Maekawa T, Kishimoto T. Growth inhibition of human leukemic cells by WT1 (Wilms tumor gene) antisense oligodeoxynucleotides: implications for the involvement of WT1 in leukemogenesis. Blood 1996; 87: 2878–84. [PubMed] [Google Scholar]
  • 19. Algar EM, Khromykh T, Smith SI, Blackburn DM, Bryson GJ, Smith PJ. A WT1 antisense oligonucleotide inhibits proliferation and induces apoptosis in myeloid leukaemia cell lines. Oncogene 1996; 12: 1005–14. [PubMed] [Google Scholar]
  • 20. Sugiyama H. Wilms' tumor gene WT1: its oncogenic function and clinical 21. application. Int J Hematol 2001; 73: 177–87. [DOI] [PubMed] [Google Scholar]
  • 21. Stewart J, Evan G, Watson J, Sikora K. Detection of the c‐myc oncogene product in colonic polyps and carcinomas. Br J Cancer 1986; 53: 1–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Yander G, Halsey H, Kenna M, Augenlicht LH. Amplification and elevated expression of c‐myc in a chemically induced mouse colon tumor. Cancer Res 1985; 45: 4433–8. [PubMed] [Google Scholar]
  • 23. Bos JL, Fearon ER, Hamilton SR, Verlaan‐de Vries M, van Boom JH, van der Eb AJ, Vogelstein B. Prevalence of ras gene mutations in human colorectal cancers. Nature 1987; 327: 293–7. [DOI] [PubMed] [Google Scholar]
  • 24. Tortola S, Marcuello E, Gonzalez I, Reyes G, Arribas R, Aiza G, Sancho FJ, Peinado MA, Capella G. p53 and K‐ras gene mutations correlate with tumor aggressiveness but are not of routine prognostic value in colorectal cancer. J Clin Oncol 1999; 17: 1375–81. [DOI] [PubMed] [Google Scholar]
  • 25. Baker SJ, Markowitz S, Fearon ER, Willson JK, Vogelstein B. Suppression of human colorectal carcinoma cell growth by wild‐type p53. Science 1990; 249: 912–5. [DOI] [PubMed] [Google Scholar]
  • 26. Rodrigues NR, Rowan A, Smith ME, Kerr IB, Bodmer WF, Gannon JV, Lane DP. p53 mutations in colorectal cancer. Proc Natl Acad Sci USA 1990; 87: 7555–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H, Horii A, Koyama K, Utsunomiya J, Baba S, Hedge P. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 1991; 253: 665–9. [DOI] [PubMed] [Google Scholar]
  • 28. Bruening W, Gros P, Sato T, Stanimir J, Nakamura Y, Housman D, Pelletier J. Analysis of the 11p13 Wilms' tumor suppressor gene (WT1) in ovarian tumors. Cancer Invest 1993; 11: 393–9. [DOI] [PubMed] [Google Scholar]
  • 29. Harada Y, Nonomura N, Nishimura K, Tamaki H, Takahara S, Miki T, Sugiyama H, Okuyama A. WT1 gene expression in human testicular germcell tumors. Mol Urol 1999; 3: 357–63. [PubMed] [Google Scholar]
  • 30. Inoue K, Tamaki H, Ogawa H, Oka Y, Soma T, Tatekawa T, Oji Y, Tsuboi A, Kim EH, Kawakami M, Akiyama T, Kishimoto T, Sugiyama H. Wilms' tumor gene (WT1) competes with differentiation‐inducing signal in hematopoietic progenitor cells. Blood 1998; 91: 2969–76. [PubMed] [Google Scholar]
  • 31. Tsuboi A, Oka Y, Ogawa H, Elisseeva OA, Tamaki H, Oji Y, Kim, EH , Soma T, Tatekawa T, Kawakami M, Kishimoto T, Sugiyama H. Constitutive expression of the Wilms' tumor gene WT1 inhibits the differentiation of myeloid progenitor cells but promotes their proliferation in response to granulocyte‐colony stimulating factor (G‐CSF). Leuk Res 1999; 23: 499–505. [DOI] [PubMed] [Google Scholar]
  • 32. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990; 61: 759–67. [DOI] [PubMed] [Google Scholar]
  • 33. Tamaki H, Ogawa H, Ohyashiki K, Ohyashiki JH, Iwama H, Inoue K, Soma T, Oka Y, Tatekawa T, Oji Y, Tsuboi A, Kim EH, Kawakami M, Fuchigami K, Tomonaga M, Toyama K, Aozasa K, Kishimoto T, Sugiyama H. The Wilms' tumor gene WT1 is a good marker for diagnosis of disease progression of myelodysplastic syndromes. Leukemia 1999; 13: 393–9. [DOI] [PubMed] [Google Scholar]
  • 34. Oka Y, Udaka K, Tsuboi A, Elisseeva OA, Ogawa H, Aozasa K, Kishimoto T, Sugiyama H. Cancer immunotherapy targeting Wilms' tumor gene WT1 product. J Immunol 2000; 164: 1873–80. [DOI] [PubMed] [Google Scholar]
  • 35. Gao L, Bellantuono I, Elsasser A, Marley SB, Gordon MY, Goldman JM, Stauss HJ. Selective elimination of leukemic CD34(+) progenitor cells by cytotoxic T lymphocytes specific for WT1. Blood 2000; 95: 2198–203. [PubMed] [Google Scholar]
  • 36. Sugiyama H. Cancer immunotherapy targeting WT1 protein. Int J Hematol 2002; 76: 127–32. [DOI] [PubMed] [Google Scholar]
  • 37. Oka Y, Tsuboi A, Elisseeva OA, Udaka K, Sugiyama H. WT1 as a novel target antigen for cancer immunotherapy. Curr Cancer Drug Targets 2002; 2: 45–54. [DOI] [PubMed] [Google Scholar]
  • 38. Oka Y, Elisseeva OA, Tsuboi A, Ogawa H, Tamaki H, Li H, Oji Y, Kim EH, Soma T, Asada M, Ueda K, Maruya E, Saji H, Kishimoto T, Udaka K, Sugiyama H. Human cytotoxic T‐lymphocyte responses specific for peptides of the wild‐type Wilms' tumor gene (WT1) product. Immunogenetics 2000; 51: 99–107. [DOI] [PubMed] [Google Scholar]
  • 39. Ohminami H, Yasukawa M, Fujita S. HLA class I‐restricted lysis of leukemia cells by a CD8(+) cytotoxic T‐lymphocyte clone specific for WT1 pep‐tide. Blood 2000; 95: 286–93. [PubMed] [Google Scholar]
  • 40. Makita M, Hiraki A, Azuma T, Tsuboi A, Oka Y, Sugiyama H, Fujita S, Tanimoto M, Harada M, Yasukawa M. Antilung cancer effect of WT1‐specific cytotoxic T lymphocytes. Clin Cancer Res 2002; 8: 2626–31. [PubMed] [Google Scholar]

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