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. 2005 Aug 19;95(10):822–827. doi: 10.1111/j.1349-7006.2004.tb02188.x

Overexpression of the Wilms' tumor gene WT1 in primary astrocytic tumors

Yusuke Oji 1, Tsuyoshi Suzuki 2, Yoko Nakano 3, Motohiko Maruno 2, Shin‐ichi Nakatsuka 4, Tanyarat Jomgeow 3, Sakie Abeno 3, Naoya Tatsumi 3, Asumi Yokota 3, Sayaka Aoyagi 3, Tsutomu Nakazawa 3, Ken Ito 3, Keisuke Kanato 3, Toshiaki Shirakata 5, Sumiyuki Nishida 5, Naoki Hosen 5, Manabu Kawakami 6, Akihiro Tsuboi 6, Yoshihiro Oka 5, Katsuyuki Aozasa 4, Toshiki Yoshimine 2, Haruo Sugiyama 3,✉
PMCID: PMC11158517  PMID: 15504250

Abstract

Expression of the Wilms' tumor gene WT1 in primary astrocytic tumors was examined using a quantitative real‐time reverse transcriptase‐polymerase chain reaction (RT‐PCR) or immunohistochemistry. Real‐time RT‐PCR showed that WT1 mRNA was expressed at various levels in all of the 25 astrocytic tumors examined. Immunohistochemical analysis showed that WT1 protein was expressed in 5 of 6 low‐grade astrocytic tumors (grade l‐ll) and all of 18 high‐grade ones (grade III‐IV), and that expression levels of WT1 protein in high‐grade tumors were significantly higher than those in low‐grade ones. WT1 protein was not detected in the normal glial cells contained in the tumor specimens. Furthermore, treatment with WT1 antisense oligomers specifically inhibited growth of glioblastoma cell lines, U87‐MG, A172, and T‐98G. These results may indicate that the WT1 gene plays an important role in tumorigenesis of primary astrocytic tumors.

References

  • 1. Call KM, Glaser TM, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Krai 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: 774–8. [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 transcriptionally repressed by the Wilms tumor suupressor 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‐α 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. 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]
  • 11. 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]
  • 12. Oji Y, Yamamoto H, Nomura M, Nakano Y, Ikeba A, Nakatsuka S, Abeno S, Kiyotoh E, Jomgeow T, Sekimoto M, Nezu R, Yoshikawa Y, Inoue Y, Hosen N, Kawakami M, Tsuboi A, Oka Y, Ogawa H, Souda S, Aozasa K, Monden M, Sugiyama H. Overexpression of the Wilms' tumor gene WT1 in colorectal adenocarcinoma. Cancer Sci 2003; 94: 712–7. [DOI] [PMC free article] [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 methylation. 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 Y, Koga S, Nakano Y, Ando A, Nakatsuka S, Ikeba A, Takahashi E, Sakaguchi N, Yokota A, Hosen N, Ikegame K, Kawakami M, Tsuboi A, Oka Y, Ogawa H, Aozasa K, Noguchi S, Sugiyama H. Overexpression of the Wilms' tumor gene WT1 in primary thyroid cancer. Cancer Sci 2003; 94: 606–11. [DOI] [PMC free article] [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; 94: 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; 94: 523–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Oji Y, Ogawa H, Tamaki H, Oka Y, Tsuboi A, Kim EH, Soma T, Tatekawa T, Kawakami M, Asada M, Kishimoto T, Suguyama 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]
  • 19. 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]
  • 20. 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]
  • 21. Sugiyama H. Wilms' tumor gene WT1: its oncogenic function and clinical application. Int J Hematol 2001; 73: 177–87. [DOI] [PubMed] [Google Scholar]
  • 22. Bigner SH, Mark J, Burger PC, Mahaley MS Jr, Bullard DE, Muhlbaier LH, Bigner DD. Specific chromosomal abnormalities in malignant human gliomas. Cancer Res 1988; 48: 405–11. [PubMed] [Google Scholar]
  • 23. Libermann TA, Nusbaum HR, Razon N, Kris R, Lax I, Soreq H, Whittle N, Waterfield MD, Ullrich A, Schlessinger J. Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature 1985; 313: 144–7. [DOI] [PubMed] [Google Scholar]
  • 24. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997; 275: 1943–7. [DOI] [PubMed] [Google Scholar]
  • 25. Schmidt EE, Ichimura K, Reifenberger G, Collins VP. CDKN2 (p16/MTSl) gene deletion or CDK4 amplification occurs in the majority of glioblastomas. Cancer Res 1994; 54: 6321–4. [PubMed] [Google Scholar]
  • 26. Tamaki H, Mishima M, Kawakami M, Tsuboi A, Kim EH, Hosen N, Ikegame K, Murakami M, Fujioka T, Masuda T, Taniguchi Y, Nishida S, Osumi K, Soma T, Oji Y, Oka Y, Kawase I, Sugiyama H, Ogawa H. Monitoring minimal residual disease in leukemia using real‐time quantitative polymerase chain reaction for Wilms tumor gene (WT1). Int J Hematol 2003; 78: 349–56. [DOI] [PubMed] [Google Scholar]
  • 27. Oji Y, Miyoshi S, Takahashi E, Koga S, Nakano Y, Shintani Y, Hirabayashi H, Matsumura A, Iuchi K, Ito K, Kishimoto Y, Tsuboi A, Ikegame K, Hosen N, Oka Y, Ogawa H, Maeda H, Hayashi S, Kawase I, Sugiyama H. Absence of mutations in the Wilms' tumor gene wt1 in de novo non‐small cell lung cancers. Neoplasms 2004; 51: 17–20. [PubMed] [Google Scholar]
  • 28. Oji Y, Miyoshi Y, Kiyotoh E, Koga S, Nakano Y, Ando A, Hosen N, Tsuboi A, Kawakami M, Ikegame K, Oka Y, Ogawa H, Noguchi S, Sugiyama H. Absence of mutations in the Wilms' tumor gene WT1 in primary breast cancer. Jpn J Clin Oncol 2004; 34: 74–7. [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: 357–64. [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). Leak Res 1999; 23: 499–505. [DOI] [PubMed] [Google Scholar]
  • 32. Dennis SL, Manji SS, Carrington DP, Scarcella DL, Ashley DM, Smith PJ, Algar EM. Expression and mutation analysis of the Wilms' tumor 1 gene in human neural tumors. Int J Cancer 2002; 97: 713–5. [DOI] [PubMed] [Google Scholar]
  • 33. Niksic M, Slight J, Sanford JR, Caceres JF, Hastie ND. The Wilms' tumour protein (WT1) shuttles between nucleus and cytoplasm and is present in functional polysomes. Hum Mol Genet 2004; 13: 463–71. [DOI] [PubMed] [Google Scholar]
  • 34. Oka Y, Udaka K, Tsuboi A, Elisseeva OA, Ogawa H, Aozasa K, Kishimoto T, Sugiyama H. Cancer immunothrapy 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, Tsuboi A, Murakami M, Hirai M, Tominaga N, Nakajima H, Elisseeva OA, Masuda T, Nakano A, Kawakami M, Oji Y, Ikegame K, Hosen N, Udaka K, Yasukawa M, Ogawa H, Kawase I, Sugiyama H. Wilms tumor gene peptide‐based immunotherapy for patients with overt leukemia from myelodysplastic syndrome (MDS) or MDS with myelofibrosis. Int J Hematol 2003; 78: 56–61. [DOI] [PubMed] [Google Scholar]
  • 39. Tsuboi A, Oka Y, Osaki T, Kumagai T, Tachibana I, Hayashi S, Murakami M, Nakajima H, Elisseeva OA, Fei W, Masuda T, Yasukawa M, Oji Y, Kawakami M, Hosen N, Ikegame K, Yoshihara S, Udaka K, Nakatsuka S, Aozasa K, Kawase I, Sugiyama H. WT1 peptide‐based Immunotherapy for patients with lung cancer: report of two cases. Microbiol Immunol 2004; 48: 175–84. [DOI] [PubMed] [Google Scholar]

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