Skip to main content
Top
Published in: Journal of Experimental & Clinical Cancer Research 1/2010

Open Access 01-12-2010 | Research

Expression and aberrant promoter methylation of Wnt inhibitory factor-1 in human astrocytomas

Authors: Zhuanyi Yang, Ying Wang, Jiasheng Fang, Fenghua Chen, Jinfang Liu, Jun Wu, Yanjin Wang

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2010

Login to get access

Abstract

Background

Wnt inhibitory factor-1(WIF-1) acts as a Wnt-antagonists and tumor suppressor, but hypermethylation of WIF-1 gene promoter and low expression activate Wnt signaling aberrantly and induce the development of various human tumors. With this work we intended to investigate the expression and promoter methylation status of WIF-1 gene in human astrocytomas.

Methods

The tissue samples consisted of 53 astrocytomas and 6 normal brain tissues. The expression levels of WIF-1 were determined by immunohistochemistry and semiquantitative RT-PCR. The results were analyzed in correlation with clinicopathological data. Methylation status of WIF-1 gene promoter was investigated using methylation specific PCR. The relationship between methylation and expression of the genes was analyzed.

Results

The average expression levels of WIF-1 protein and mRNA in astrocytomas were decreased significantly compared with normal control tissues. The protein and mRNA expression of WIF-1 gene in astrocytomas was decreased with the increase of pathological grade. Furthermore, WIF-1 promoter methylation was observed by MS-PCR in astrocytomas which showed significant reduction of WIF-1 expression. The WIF-1 promoter hypermethylation was associated with reduced expression of WIF-1 expression.

Conclusion

Our results demonstrate that the WIF-1 gene is frequently down-regulated or silenced in astrocytomas by aberrant promoter methylation. This may be an important mechanism in astrocytoma carcinogenesis.
Appendix
Available only for authorised users
Literature
1.
go back to reference Wen PY, Kesari S: Malignant astrocytomas in adults. N Engl J Med. 2008, 359: 492-507. 10.1056/NEJMra0708126.CrossRef Wen PY, Kesari S: Malignant astrocytomas in adults. N Engl J Med. 2008, 359: 492-507. 10.1056/NEJMra0708126.CrossRef
2.
go back to reference Pu P, Zhang Z, Kang C, Jiang R, Jia Z, Wang G, Jiang H: Downregulation of Wnt2 and beta-catenin by siRNA suppresses malignant astrocytoma cell growth. Cancer Gene Ther. 2009, 16: 351-361. 10.1038/cgt.2008.78.CrossRef Pu P, Zhang Z, Kang C, Jiang R, Jia Z, Wang G, Jiang H: Downregulation of Wnt2 and beta-catenin by siRNA suppresses malignant astrocytoma cell growth. Cancer Gene Ther. 2009, 16: 351-361. 10.1038/cgt.2008.78.CrossRef
3.
go back to reference Yu JM, Jun ES, Jung JS, Suh SY, Han JY, Kim JY, Kim KW, Jung JS: Role of Wnt5a in the proliferation of human glioblastoma cells. Cancer Lett. 2007, 257: 172-181. 10.1016/j.canlet.2007.07.011.CrossRef Yu JM, Jun ES, Jung JS, Suh SY, Han JY, Kim JY, Kim KW, Jung JS: Role of Wnt5a in the proliferation of human glioblastoma cells. Cancer Lett. 2007, 257: 172-181. 10.1016/j.canlet.2007.07.011.CrossRef
4.
go back to reference Sareddy GR, Challa S, Panigrahi M, Babu PP: Wnt/beta-catenin/Tcf signaling pathway activation in malignant progression of rat astrocytomas induced by transplacental N-ethyl-N-nitrosourea exposure. Neurochem Res. 2009, 34: 1278-188. 10.1007/s11064-008-9906-3.CrossRef Sareddy GR, Challa S, Panigrahi M, Babu PP: Wnt/beta-catenin/Tcf signaling pathway activation in malignant progression of rat astrocytomas induced by transplacental N-ethyl-N-nitrosourea exposure. Neurochem Res. 2009, 34: 1278-188. 10.1007/s11064-008-9906-3.CrossRef
5.
go back to reference Sareddy GR, Panigrahi M, Challa S, Mahadevan A, Babu PP: Activation of Wnt/beta-catenin/Tcf signaling pathway in human astrocytomas. Neurochem Int. 2009, 55: 307-317. 10.1016/j.neuint.2009.03.016.CrossRef Sareddy GR, Panigrahi M, Challa S, Mahadevan A, Babu PP: Activation of Wnt/beta-catenin/Tcf signaling pathway in human astrocytomas. Neurochem Int. 2009, 55: 307-317. 10.1016/j.neuint.2009.03.016.CrossRef
6.
go back to reference Hsieh JC, Kodjabachian L, Rebbert ML, Rattner A, Smallwood PM, Samos CH, Nusse R, Dawid IB, Nathans J: A new secreted protein that binds to Wnt proteins and inhibits their activities. Nature. 1999, 398: 431-436. 10.1038/18899.CrossRef Hsieh JC, Kodjabachian L, Rebbert ML, Rattner A, Smallwood PM, Samos CH, Nusse R, Dawid IB, Nathans J: A new secreted protein that binds to Wnt proteins and inhibits their activities. Nature. 1999, 398: 431-436. 10.1038/18899.CrossRef
7.
go back to reference Ding Z, Qian YB, Zhu LX, Xiong QR: Promoter methylation and mRNA expression of DKK-3 and WIF-1 in hepatocellular carcinoma. World J Gastroenterol. 2009, 15: 2595-2601. 10.3748/wjg.15.2595.CrossRef Ding Z, Qian YB, Zhu LX, Xiong QR: Promoter methylation and mRNA expression of DKK-3 and WIF-1 in hepatocellular carcinoma. World J Gastroenterol. 2009, 15: 2595-2601. 10.3748/wjg.15.2595.CrossRef
8.
go back to reference Lin YC, You L, Xu Z, He B, Mikami I, Thung E, Chou J, Kuchenbecker K, Kim J, Raz D, Yang CT, Chen JK, Jablons DM: Wnt signaling activation and WIF-1 silencing in nasopharyngeal cancer cell lines. Biochem Biophys Res Commun. 2006, 341: 635-640. 10.1016/j.bbrc.2005.12.220.CrossRef Lin YC, You L, Xu Z, He B, Mikami I, Thung E, Chou J, Kuchenbecker K, Kim J, Raz D, Yang CT, Chen JK, Jablons DM: Wnt signaling activation and WIF-1 silencing in nasopharyngeal cancer cell lines. Biochem Biophys Res Commun. 2006, 341: 635-640. 10.1016/j.bbrc.2005.12.220.CrossRef
9.
go back to reference Mazieres J, He B, You L, Xu Z, Lee AY, Mikami I, Reguart N, Rosell R, McCormick F, Jablons DM: Wnt inhibitory factor-1 is silenced by promoter hypermethylation in human lung cancer. Cancer Res. 2004, 64: 4717-4720. 10.1158/0008-5472.CAN-04-1389.CrossRef Mazieres J, He B, You L, Xu Z, Lee AY, Mikami I, Reguart N, Rosell R, McCormick F, Jablons DM: Wnt inhibitory factor-1 is silenced by promoter hypermethylation in human lung cancer. Cancer Res. 2004, 64: 4717-4720. 10.1158/0008-5472.CAN-04-1389.CrossRef
10.
go back to reference Urakami S, Shiina H, Enokida H, Kawakami T, Tokizane T, Ogishima T, Tanaka Y, Li LC, Ribeiro-Filho LA, Terashima M, Kikuno N, Adachi H, Yoneda T, Kishi H, Shigeno K, Konety BR, Igawa M, Dahiya R: Epigenetic inactivation of Wnt inhibitory factor-1 plays an important role in bladder cancer through aberrant canonical Wnt/beta-catenin signaling pathway. Clin Cancer Res. 2006, 12: 383-391. 10.1158/1078-0432.CCR-05-1344.CrossRef Urakami S, Shiina H, Enokida H, Kawakami T, Tokizane T, Ogishima T, Tanaka Y, Li LC, Ribeiro-Filho LA, Terashima M, Kikuno N, Adachi H, Yoneda T, Kishi H, Shigeno K, Konety BR, Igawa M, Dahiya R: Epigenetic inactivation of Wnt inhibitory factor-1 plays an important role in bladder cancer through aberrant canonical Wnt/beta-catenin signaling pathway. Clin Cancer Res. 2006, 12: 383-391. 10.1158/1078-0432.CCR-05-1344.CrossRef
11.
go back to reference Taniguchi H, Yamamoto H, Hirata T, Miyamoto N, Oki M, Nosho K, Adachi Y, Endo T, mai K, Shinomura Y: Frequent epigenetic inactivation of Wnt inhibitory factor-1 in human gastrointestinal cancers. Oncogene. 2005, 24: 7946-7952. 10.1038/sj.onc.1208910.CrossRef Taniguchi H, Yamamoto H, Hirata T, Miyamoto N, Oki M, Nosho K, Adachi Y, Endo T, mai K, Shinomura Y: Frequent epigenetic inactivation of Wnt inhibitory factor-1 in human gastrointestinal cancers. Oncogene. 2005, 24: 7946-7952. 10.1038/sj.onc.1208910.CrossRef
12.
go back to reference Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007, 114: 97-109. 10.1007/s00401-007-0243-4.CrossRef Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007, 114: 97-109. 10.1007/s00401-007-0243-4.CrossRef
13.
go back to reference Joki T, Heese O, Nikas DC, Bello L, Zhang J, Kraeft SK, Seyfried NT, Abe T, Chen LB, Carroll RS, Black PM: Expression of cyclooxygenase 2 (COX-2) in human glioma and in vitro inhibition by a specific COX-2 inhibitor, NS-398. Cancer Res. 2000, 60: 4926-4931. Joki T, Heese O, Nikas DC, Bello L, Zhang J, Kraeft SK, Seyfried NT, Abe T, Chen LB, Carroll RS, Black PM: Expression of cyclooxygenase 2 (COX-2) in human glioma and in vitro inhibition by a specific COX-2 inhibitor, NS-398. Cancer Res. 2000, 60: 4926-4931.
14.
go back to reference Reguart N, He B, Xu Z, You L, Lee AY, Mazieres J, Mikami I, Batra S, Rosell R, McCormick F, Jablons DM: Cloning and characterization of the promoter of human Wnt inhibitory factor-1. Biochem Biophys Res Commun. 2004, 323: 229-234. 10.1016/j.bbrc.2004.08.075.CrossRef Reguart N, He B, Xu Z, You L, Lee AY, Mazieres J, Mikami I, Batra S, Rosell R, McCormick F, Jablons DM: Cloning and characterization of the promoter of human Wnt inhibitory factor-1. Biochem Biophys Res Commun. 2004, 323: 229-234. 10.1016/j.bbrc.2004.08.075.CrossRef
15.
go back to reference Turashvili G, Bouchal J, Burkadze G, Kolar Z: Wnt signaling pathway in mammary gland development and carcinogenesis. Pathobiology. 2006, 73: 213-223. 10.1159/000098207.CrossRef Turashvili G, Bouchal J, Burkadze G, Kolar Z: Wnt signaling pathway in mammary gland development and carcinogenesis. Pathobiology. 2006, 73: 213-223. 10.1159/000098207.CrossRef
16.
go back to reference Fodde R, Brabletz T: Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Curr Opin Cell Biol. 2007, 19: 150-158. 10.1016/j.ceb.2007.02.007.CrossRef Fodde R, Brabletz T: Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Curr Opin Cell Biol. 2007, 19: 150-158. 10.1016/j.ceb.2007.02.007.CrossRef
17.
go back to reference Shiina H, Igawa M, Breault J, Ribeiro-Filho L, Pookot D, Urakami S, Terashima M, Deguchi M, Yamanaka M, Shirai M, Kaneuchi M, Kane CJ, Dahiya R: The human T-cell factor-4 gene splicing isoforms, Wnt signal pathway, and apoptosis in renal cell carcinoma. Clin Cancer Res. 2003, 9: 2121-2132. Shiina H, Igawa M, Breault J, Ribeiro-Filho L, Pookot D, Urakami S, Terashima M, Deguchi M, Yamanaka M, Shirai M, Kaneuchi M, Kane CJ, Dahiya R: The human T-cell factor-4 gene splicing isoforms, Wnt signal pathway, and apoptosis in renal cell carcinoma. Clin Cancer Res. 2003, 9: 2121-2132.
18.
go back to reference He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW: Identification of c-MYC as a target of the APC pathway. Science. 1998, 281: 1509-1512. 10.1126/science.281.5382.1509.CrossRef He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW: Identification of c-MYC as a target of the APC pathway. Science. 1998, 281: 1509-1512. 10.1126/science.281.5382.1509.CrossRef
19.
go back to reference Tetsu O, McCormick F: Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature. 1999, 398: 422-426. 10.1038/18884.CrossRef Tetsu O, McCormick F: Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature. 1999, 398: 422-426. 10.1038/18884.CrossRef
20.
go back to reference Kawano Y, Kypta R: Secreted antagonists of the Wnt signalling pathway. J Cell Sci. 2003, 116: 2627-34. 10.1242/jcs.00623.CrossRef Kawano Y, Kypta R: Secreted antagonists of the Wnt signalling pathway. J Cell Sci. 2003, 116: 2627-34. 10.1242/jcs.00623.CrossRef
21.
go back to reference Hu YA, Gu X, Liu J, Yang Y, Yan Y, Zhao C: Expression pattern of Wnt inhibitor factor 1(Wif1) during the development in mouse CNS. Gene Expr Patterns. 2008, 8: 515-522. 10.1016/j.gep.2008.06.001.CrossRef Hu YA, Gu X, Liu J, Yang Y, Yan Y, Zhao C: Expression pattern of Wnt inhibitor factor 1(Wif1) during the development in mouse CNS. Gene Expr Patterns. 2008, 8: 515-522. 10.1016/j.gep.2008.06.001.CrossRef
22.
go back to reference Jones PA, Baylin SB: The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002, 3: 415-428. 10.1038/nrg962.CrossRef Jones PA, Baylin SB: The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002, 3: 415-428. 10.1038/nrg962.CrossRef
23.
go back to reference Herman JG, Baylin SB: Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003, 349: 2042-2054. 10.1056/NEJMra023075.CrossRef Herman JG, Baylin SB: Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003, 349: 2042-2054. 10.1056/NEJMra023075.CrossRef
24.
go back to reference Vladimirova V, Mikeska T, Waha A, Soerensen N, Xu J, Reynolds PC, Pietsch T: Aberrant methylation and reduced expression of LHX9 in malignant astrocytomas of childhood. Neoplasia. 2009, 11: 700-711.CrossRef Vladimirova V, Mikeska T, Waha A, Soerensen N, Xu J, Reynolds PC, Pietsch T: Aberrant methylation and reduced expression of LHX9 in malignant astrocytomas of childhood. Neoplasia. 2009, 11: 700-711.CrossRef
25.
go back to reference Blanc JL, Wager M, Guilhot J, Kusy S, Bataille B, Chantereau T, Lapierre F, Larsen CJ, Karayan-Tapon L: Correlation of clinical features and methylation status of MGMT gene promoter in glioblastomas. J Neurooncol. 2004, 68: 275-283. 10.1023/B:NEON.0000033385.37098.85.CrossRef Blanc JL, Wager M, Guilhot J, Kusy S, Bataille B, Chantereau T, Lapierre F, Larsen CJ, Karayan-Tapon L: Correlation of clinical features and methylation status of MGMT gene promoter in glioblastomas. J Neurooncol. 2004, 68: 275-283. 10.1023/B:NEON.0000033385.37098.85.CrossRef
26.
go back to reference Schmidt EE, Ichimura K, Messerle KR, Goike HM, Collins VP: Infrequent methylation of CDKN2A(MTS1/p16) and rare mutation of both CDKN2A and CDKN2B(MTS2/p15) in primary astrocytic tumours. Br J Cancer. 1997, 75: 2-8.CrossRef Schmidt EE, Ichimura K, Messerle KR, Goike HM, Collins VP: Infrequent methylation of CDKN2A(MTS1/p16) and rare mutation of both CDKN2A and CDKN2B(MTS2/p15) in primary astrocytic tumours. Br J Cancer. 1997, 75: 2-8.CrossRef
27.
go back to reference Wiencke JK, Zheng S, Jelluma N, Tihan T, Vandenberg S, Tamguney T, Baumber R, Parsons R, Lamborn KR, Berger MS, Wrensch MR, Haas-Kogan DA, Stokoe D: Methylation of the PTEN promoter defines low-grade astrocytomas and secondary glioblastoma. Neuro Oncol. 2007, 9: 271-279. 10.1215/15228517-2007-003.CrossRef Wiencke JK, Zheng S, Jelluma N, Tihan T, Vandenberg S, Tamguney T, Baumber R, Parsons R, Lamborn KR, Berger MS, Wrensch MR, Haas-Kogan DA, Stokoe D: Methylation of the PTEN promoter defines low-grade astrocytomas and secondary glioblastoma. Neuro Oncol. 2007, 9: 271-279. 10.1215/15228517-2007-003.CrossRef
28.
go back to reference Wemmert S, Bettscheider M, Alt S, Ketter R, Kammers K, Feiden W, Steudel WI, Rahnenfuhrer J, Urbschat S: p15 promoter methylation - a novel prognostic marker in glioblastoma patients. Int J Oncol. 2009, 34: 1743-1748. Wemmert S, Bettscheider M, Alt S, Ketter R, Kammers K, Feiden W, Steudel WI, Rahnenfuhrer J, Urbschat S: p15 promoter methylation - a novel prognostic marker in glioblastoma patients. Int J Oncol. 2009, 34: 1743-1748.
29.
go back to reference Wissmann C, Wild PJ, Kaiser S, Roepcke S, Stoehr R, Woenckhaus M, Kristiansen G, Hsieh JC, Hofstaedter F, Hartmann A, Knuechel R, Rosenthal A, Pilarsky C: WIF1, a component of the Wnt pathway, is down-regulated in prostate, breast, lung, and bladder cancer. J Pathol. 2003, 201: 204-212. 10.1002/path.1449.CrossRef Wissmann C, Wild PJ, Kaiser S, Roepcke S, Stoehr R, Woenckhaus M, Kristiansen G, Hsieh JC, Hofstaedter F, Hartmann A, Knuechel R, Rosenthal A, Pilarsky C: WIF1, a component of the Wnt pathway, is down-regulated in prostate, breast, lung, and bladder cancer. J Pathol. 2003, 201: 204-212. 10.1002/path.1449.CrossRef
Metadata
Title
Expression and aberrant promoter methylation of Wnt inhibitory factor-1 in human astrocytomas
Authors
Zhuanyi Yang
Ying Wang
Jiasheng Fang
Fenghua Chen
Jinfang Liu
Jun Wu
Yanjin Wang
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2010
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/1756-9966-29-26

Other articles of this Issue 1/2010

Journal of Experimental & Clinical Cancer Research 1/2010 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine