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XEDAR as a putative colorectal tumor suppressor that mediates p53-regulated anoikis pathway

Oncogene volume 28, pages 3081–3092 (2009)Cite this article

Abstract

Colorectal cancers with mutations in the p53 gene have an invasive property, but its underlying mechanism is not fully understood. Through the screening of two data sets of the genome-wide expression profile, one for p53-introduced cells and the other for the numbers of cancer tissues, we report here X-linked ectodermal dysplasia receptor (XEDAR), a member of the TNFR superfamily, as a novel p53 target that has a crucial role in colorectal carcinogenesis. p53 upregulated XEDAR expression through two p53-binding sites within intron 1 of the XEDAR gene. We also found a significant correlation between decreased XEDAR expressions and p53 gene mutations in breast and lung cancer cell lines (P=0.0043 and P=0.0122, respectively). Furthermore, promoter hypermethylation of the XEDAR gene was detected in 20 of 20 colorectal cancer cell lines (100%) and in 6 of 12 colorectal cancer tissues (50%), respectively. Thus, the XEDAR expression was suppressed to <25% of surrounding normal tissues in 12 of 18 colorectal cancer tissues (66.7%) due to either its epigenetic alterations and/or p53 mutations. We also found that XEDAR interacted with and subsequently caused the accumulation of FAS protein, another member of p53-inducible TNFR. Moreover, XEDAR negatively regulated FAK, a central component of focal adhesion. As a result, inactivation of XEDAR resulted in the enhancement of cell adhesion and spreading, as well as resistance to p53-induced apoptosis. Taken together, our findings showed that XEDAR is a putative tumor suppressor that could prevent malignant transformation and tumor progression by regulating apoptosis and anoikis.

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References

  • Afford SC, Randhawa S, Eliopoulos AG, Hubscher SG, Young LS, Adams DH . (1999). CD40 activation induces apoptosis in cultured human hepatocytes via induction of cell surface fas ligand expression and amplifies fas-mediated hepatocyte death during allograft rejection. J Exp Med 189: 441–446.

    Article  CAS  Google Scholar 

  • Beroud C, Soussi T . (2003). The UMD-p53 database: new mutations and analysis tools. Hum Mutat 21: 176–181.

    Article  CAS  Google Scholar 

  • Diez M, Medrano M, Muguerza JM, Ramos P, Hernandez P, Villeta R et al. (2000). Influence of tumor localization on the prognostic value of P53 protein in colorectal adenocarcinomas. Anticancer Res 20: 3907–3912.

    CAS  PubMed  Google Scholar 

  • Folkman J, Moscona A . (1978). Role of cell shape in growth control. Nature 273: 345–349.

    Article  CAS  Google Scholar 

  • Furutani M, Arii S, Tanaka H, Mise M, Niwano M, Harada T et al. (1997). Decreased expression and rare somatic mutation of the CIP1/WAF1 gene in human hepatocellular carcinoma. Cancer Lett 111: 191–197.

    Article  CAS  Google Scholar 

  • Golubovskaya VM, Finch R, Kweh F, Massoll NA, Campbell-Thompson M, Wallace MR et al. (2008). p53 regulates FAK expression in human tumor cells. Mol Carcinog 47: 373–382.

    Article  CAS  Google Scholar 

  • Grell M, Zimmermann G, Gottfried E, Chen CM, Grunwald U, Huang DC et al. (1999). Induction of cell death by tumour necrosis factor (TNF) receptor 2, CD40 and CD30: a role for TNF-R1 activation by endogenous membrane-anchored TNF. EMBO J 18: 3034–3043.

    Article  CAS  Google Scholar 

  • Hollstein M, Rice K, Greenblatt MS, Soussi T, Fuchs R, Sorlie T et al. (1994). Database of p53 gene somatic mutations in human tumors and cell lines. Nucleic Acids Res 22: 3551–3555.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ilic D, Almeida EA, Schlaepfer DD, Dazin P, Aizawa S, Damsky CH . (1998). Extracellular matrix survival signals transduced by focal adhesion kinase suppress p53-mediated apoptosis. J Cell Biol 143: 547–560.

    Article  CAS  Google Scholar 

  • Ilic D, Furuta Y, Kanazawa S, Takeda N, Sobue K, Nakatsuji N et al. (1995). Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature 377: 539–544.

    Article  CAS  Google Scholar 

  • Kidokoro T, Tanikawa C, Furukawa Y, Katagiri T, Nakamura Y, Matsuda K . (2008). CDC20, a potential cancer therapeutic target, is negatively regulated by p53. Oncogene 27: 1562–1571.

    Article  CAS  Google Scholar 

  • Kitahara O, Furukawa Y, Tanaka T, Kihara C, Ono K, Yanagawa R et al. (2001). Alterations of gene expression during colorectal carcinogenesis revealed by cDNA microarrays after laser-capture microdissection of tumor tissues and normal epithelia. Cancer Res 61: 3544–3549.

    CAS  PubMed  Google Scholar 

  • Lark AL, Livasy CA, Calvo B, Caskey L, Moore DT, Yang X et al. (2003). Overexpression of focal adhesion kinase in primary colorectal carcinomas and colorectal liver metastases: immunohistochemistry and real-time PCR analyses. Clin Cancer Res 9: 215–222.

    CAS  PubMed  Google Scholar 

  • Lee SH, Shin MS, Kim HS, Lee HK, Park WS, Kim SY et al. (1999). Alterations of the DR5/TRAIL receptor 2 gene in non-small cell lung cancers. Cancer Res 59: 5683–5686.

    CAS  PubMed  Google Scholar 

  • Levine AJ . (1997). p53, the cellular gatekeeper for growth and division. Cell 88: 323–331.

    Article  CAS  Google Scholar 

  • Liang F, Liang J, Wang WQ, Sun JP, Udho E, Zhang ZY . (2007). PRL3 promotes cell invasion and proliferation by down-regulation of Csk leading to Src activation. J Biol Chem 282: 5413–5419.

    Article  CAS  Google Scholar 

  • Liu X, Yue P, Khuri FR, Sun SY . (2005). Decoy receptor 2 (DcR2) is a p53 target gene and regulates chemosensitivity. Cancer Res 65: 9169–9175.

    Article  CAS  Google Scholar 

  • Matsuda K, Yoshida K, Taya Y, Nakamura K, Nakamura Y, Arakawa H . (2002). p53AIP1 regulates the mitochondrial apoptotic pathway. Cancer Res 62: 2883–2889.

    CAS  PubMed  Google Scholar 

  • McLean GW, Carragher NO, Avizienyte E, Evans J, Brunton VG, Frame MC . (2005). The role of focal-adhesion kinase in cancer—a new therapeutic opportunity. Nat Rev Cancer 5: 505–515.

    Article  CAS  Google Scholar 

  • Mori T, Anazawa Y, Iiizumi M, Fukuda S, Nakamura Y, Arakawa H . (2002). Identification of the interferon regulatory factor 5 gene (IRF-5) as a direct target for p53. Oncogene 21: 2914–2918.

    Article  CAS  Google Scholar 

  • Naito A, Yoshida H, Nishioka E, Satoh M, Azuma S, Yamamoto T et al. (2002). TRAF6-deficient mice display hypohidrotic ectodermal dysplasia. Proc Natl Acad Sci USA 99: 8766–8771.

    Article  CAS  Google Scholar 

  • Nakamura Y . (2004). Isolation of p53-target genes and their functional analysis. Cancer Sci 95: 7–11.

    Article  CAS  Google Scholar 

  • Newton K, French DM, Yan M, Frantz GD, Dixit VM . (2004). Myodegeneration in EDA-A2 transgenic mice is prevented by XEDAR deficiency. Mol Cell Biol 24: 1608–1613.

    Article  CAS  Google Scholar 

  • Nikiforov MA, Hagen K, Ossovskaya VS, Connor TM, Lowe SW, Deichman GI et al. (1996). p53 modulation of anchorage independent growth and experimental metastasis. Oncogene 13: 1709–1719.

    CAS  PubMed  Google Scholar 

  • Oda K, Arakawa H, Tanaka T, Matsuda K, Tanikawa C, Mori T et al. (2000). p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser-46-phosphorylated p53. Cell 102: 849–862.

    Article  CAS  Google Scholar 

  • Owens LV, Xu L, Craven RJ, Dent GA, Weiner TM, Kornberg L et al. (1995). Overexpression of the focal adhesion kinase (p125FAK) in invasive human tumors. Cancer Res 55: 2752–2755.

    CAS  PubMed  Google Scholar 

  • Pharoah PD, Day NE, Caldas C . (1999). Somatic mutations in the p53 gene and prognosis in breast cancer: a meta-analysis. Br J Cancer 80: 1968–1973.

    Article  CAS  Google Scholar 

  • Rampino N, Yamamoto H, Ionov Y, Li Y, Sawai H, Reed JC et al. (1997). Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science 275: 967–969.

    Article  CAS  Google Scholar 

  • Sinha SK, Chaudhary PM . (2004). Induction of apoptosis by X-linked ectodermal dysplasia receptor via a caspase 8-dependent mechanism. J Biol Chem 279: 41873–41881.

    Article  CAS  Google Scholar 

  • Sinha SK, Zachariah S, Quinones HI, Shindo M, Chaudhary PM . (2002). Role of TRAF3 and -6 in the activation of the NF-kappa B and JNK pathways by X-linked ectodermal dysplasia receptor. J Biol Chem 277: 44953–44961.

    Article  CAS  Google Scholar 

  • Smahi A, Courtois G, Rabia SH, Doffinger R, Bodemer C, Munnich A et al. (2002). The NF-kappaB signalling pathway in human diseases: from incontinentia pigmenti to ectodermal dysplasias and immune-deficiency syndromes. Hum Mol Genet 11: 2371–2375.

    Article  CAS  Google Scholar 

  • Takakuwa T, Dong Z, Nakatsuka S, Kojya S, Harabuchi Y, Yang WI et al. (2002). Frequent mutations of Fas gene in nasal NK/T cell lymphoma. Oncogene 21: 4702–4705.

    Article  CAS  Google Scholar 

  • Tanaka H, Arakawa H, Yamaguchi T, Shiraishi K, Fukuda S, Matsui K et al. (2000). A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage. Nature 404: 42–49.

    Article  CAS  Google Scholar 

  • Tanikawa C, Matsuda K, Fukuda S, Nakamura Y, Arakawa H . (2003). p53RDL1 regulates p53-dependent apoptosis. Nat Cell Biol 5: 216–223.

    Article  CAS  Google Scholar 

  • Vogelstein B, Fearon ER, Kern SE, Hamilton SR, Preisinger AC, Nakamura Y et al. (1989). Allelotype of colorectal carcinomas. Science 244: 207–211.

    Article  CAS  Google Scholar 

  • Vogelstein B, Lane D, Levine AJ . (2000). Surfing the p53 network. Nature 408: 307–310.

    Article  CAS  Google Scholar 

  • Weiner TM, Liu ET, Craven RJ, Cance WG . (1993). Expression of focal adhesion kinase gene and invasive cancer. Lancet 342: 1024–1025.

    Article  CAS  Google Scholar 

  • Wu GS, Burns TF, McDonald III ER, Jiang W, Meng R, Krantz ID et al. (1997). KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nat Genet 17: 141–143.

    Article  CAS  Google Scholar 

  • Yan M, Wang LC, Hymowitz SG, Schilbach S, Lee J, Goddard A et al. (2000). Two-amino acid molecular switch in an epithelial morphogen that regulates binding to two distinct receptors. Science 290: 523–527.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank T Katagiri for helpful discussion and A Takahashi K Makino for her technical assistance. This work was supported partly by grant #18687012 from Japan Society for the Promotion of Science and Ministry of education, culture, sports, science and technology of Japan (to KM). CT is a JSPS Research Fellow.

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Authors and Affiliations

  1. Laboratory of Molecular Medicine, Human Genome Center, The University of Tokyo, Tokyo, Japan

    C Tanikawa, Y Nakamura & K Matsuda

  2. Division of Clinical Genome Research, The University of Tokyo, Tokyo, Japan

    Y Furukawa

  3. Division of Gene Expression and Regulation, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    C Tanikawa & N Yoshida

  4. Cancer Medicine and Biophysics Division, National Cancer Center Research Institute, Tokyo, Japan

    H Arakawa

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  1. C Tanikawa
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  2. Y Furukawa
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Correspondence to K Matsuda.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Tanikawa, C., Furukawa, Y., Yoshida, N. et al. XEDAR as a putative colorectal tumor suppressor that mediates p53-regulated anoikis pathway. Oncogene 28, 3081–3092 (2009). https://doi.org/10.1038/onc.2009.154

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