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Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling

Oncogene volume 28, pages 297–305 (2009)Cite this article

Abstract

The Wnt signaling pathway is involved in normal embryonic development and controls the homeostatic self-renewal of stem cells in adult tissues. Constitutive activation of Wnt signaling contributes to cancer development and progression. We identified a CXXC4 homozygous deletion at 4q24 in an aggressive renal cell carcinoma (RCC) using single-nucleotide polymorphism (SNP) arrays. CXXC4 encodes Idax, which negatively regulates Wnt signaling by binding to the PDZ domain of Dishevelled. CXXC4 mRNA levels in tumor samples were significantly lower in patients with metastases compared with those without (P=0.0016). Patients whose tumors had lower CXXC4 expression than normal kidney showed a poorer cause-specific survival outcome than those with higher expression (P=0.0095). Decreased expression of CXXC4 also correlated with cytoplasmic staining of β-catenin. Knockdown of CXXC4 induced the nuclear translocation of β-catenin and altered expression of a set of genes involved in cell proliferation, invasion and survival. Furthermore, reduced expression of CXXC4 by small interfering RNAs promoted cell proliferation and inhibited apoptosis after 5-FU and doxorubicin treatment in RCC cells. These data suggest that CXXC4 plays a critical role in tumor progression of RCC through Wnt signaling. Wnt signaling could thus be a potential molecular target in RCC indicating decreased CXXC4 expression.

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References

  • Barker N, Clevers H . (2006). Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discov 5: 997–1014.

    Article  CAS  PubMed  Google Scholar 

  • Bignell GR, Huang J, Greshock J, Watt S, Butler A, West S et al. (2004). High-resolution analysis of DNA copy number using oligonucleotide microarrays. Genome Res 14: 287–295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bilim V, Kawasaki T, Katagiri A, Wakatsuki S, Takahashi K, Tomita Y . (2000). Altered expression of beta-catenin in renal cell cancer and transitional cell cancer with the absence of beta-catenin gene mutations. Clin Cancer Res 6: 460–466.

    CAS  PubMed  Google Scholar 

  • Cohen HT, McGovern FJ . (2005). Renal-cell carcinoma. N Engl J Med 353: 2477–2490.

    Article  CAS  PubMed  Google Scholar 

  • Crnkovic-Mertens I, Wagener N, Semzow J, Grone EF, Haferkamp A, Hohenfellner M et al. (2007). Targeted inhibition of Livin resensitizes renal cancer cells towards apoptosis. Cell Mol Life Sci 64: 1137–1144.

    Article  CAS  PubMed  Google Scholar 

  • Dahl E, Wiesmann F, Woenckhaus M, Stoehr R, Wild PJ, Veeck J et al. (2007). Frequent loss of SFRP1 expression in multiple human solid tumours: association with aberrant promoter methylation in renal cell carcinoma. Oncogene 26: 5680–5691.

    Article  CAS  PubMed  Google Scholar 

  • Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M et al. (2007). Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356: 125–134.

    Article  CAS  PubMed  Google Scholar 

  • Gavert N, Conacci-Sorrell M, Gast D, Schneider A, Altevogt P, Brabletz T et al. (2005). L1, a novel target of beta-catenin signaling, transforms cells and is expressed at the invasive front of colon cancers. J Cell Biol 168: 633–642.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guinan P, Sobin LH, Algaba F, Badellino F, Kameyama S, MacLennan G et al. (1997). TNM staging of renal cell carcinoma: Workgroup No. 3. Union International Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer 80: 992–993.

    Article  CAS  PubMed  Google Scholar 

  • Gumz ML, Zou H, Kreinest PA, Childs AC, Belmonte LS, LeGrand SN et al. (2007). Secreted frizzled-related protein 1 loss contributes to tumor phenotype of clear cell renal cell carcinoma. Clin Cancer Res 13: 4740–4749.

    Article  CAS  PubMed  Google Scholar 

  • Hino S, Kishida S, Michiue T, Fukui A, Sakamoto I, Takada S et al. (2001). Inhibition of the Wnt signaling pathway by Idax, a novel Dvl-binding protein. Mol Cell Biol 21: 330–342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang F, Desper R, Papadimitriou CH, Schaffer AA, Kallioniemi OP, Richter J et al. (2000). Construction of evolutionary tree models for renal cell carcinoma from comparative genomic hybridization data. Cancer Res 60: 6503–6509.

    CAS  PubMed  Google Scholar 

  • Jiang F, Moch H, Richter J, Egenter C, Gasser T, Bubendorf L et al. (1998). Comparative genomic hybridization reveals frequent chromosome 13q and 4q losses in renal carcinomas with sarcomatoid transformation. J Pathol 185: 382–388.

    Article  CAS  PubMed  Google Scholar 

  • Kasof GM, Gomes BC . (2001). Livin, a novel inhibitor of apoptosis protein family member. J Biol Chem 276: 3238–3246.

    Article  CAS  PubMed  Google Scholar 

  • Kempkensteffen C, Hinz S, Schrader M, Christoph F, Magheli A, Krause H et al. (2007). Gene expression and promoter methylation of the XIAP-associated factor 1 in renal cell carcinomas: correlations with pathology and outcome. Cancer Lett 254: 227–235.

    Article  CAS  PubMed  Google Scholar 

  • Krig SR, Jin VX, Bieda MC, O'Geen H, Yaswen P, Green R et al. (2007). Identification of genes directly regulated by the oncogene ZNF217 using chromatin immunoprecipitation (ChIP)-chip assays. J Biol Chem 282: 9703–9712.

    Article  CAS  PubMed  Google Scholar 

  • Kurose K, Sakaguchi M, Nasu Y, Ebara S, Kaku H, Kariyama R et al. (2004). Decreased expression of REIC/Dkk-3 in human renal clear cell carcinoma. J Urol 171: 1314–1318.

    Article  CAS  PubMed  Google Scholar 

  • Lee MG, Huh JS, Chung SK, Lee JH, Byun DS, Ryu BK et al. (2006). Promoter CpG hypermethylation and downregulation of XAF1 expression in human urogenital malignancies: implication for attenuated p53 response to apoptotic stresses. Oncogene 25: 5807–5822.

    Article  CAS  PubMed  Google Scholar 

  • Levy DA, Slaton JW, Swanson DA, Dinney CP . (1998). Stage specific guidelines for surveillance after radical nephrectomy for local renal cell carcinoma. J Urol 159: 1163–1167.

    Article  CAS  PubMed  Google Scholar 

  • Liston P, Fong WG, Kelly NL, Toji S, Miyazaki T, Conte D et al. (2001). Identification of XAF1 as an antagonist of XIAP anti-caspase activity. Nat Cell Biol 3: 128–133.

    Article  CAS  PubMed  Google Scholar 

  • Mann B, Gelos M, Siedow A, Hanski ML, Gratchev A, Ilyas M et al. (1999). Target genes of beta-catenin-T cell-factor/lymphoid-enhancer-factor signaling in human colorectal carcinomas. Proc Natl Acad Sci USA 96: 1603–1608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsuzaki H, Dong S, Loi H, Di X, Liu G, Hubbell E et al. (2004). Genotyping over 100,000 SNPs on a pair of oligonucleotide arrays. Nat Methods 1: 109–111.

    Article  CAS  PubMed  Google Scholar 

  • Michiue T, Fukui A, Yukita A, Sakurai K, Danno H, Kikuchi A et al. (2004). XIdax, an inhibitor of the canonical Wnt pathway, is required for anterior neural structure formation in Xenopus. Dev Dyn 230: 79–90.

    Article  CAS  PubMed  Google Scholar 

  • Mitra AB, Murty VV, Li RG, Pratap M, Luthra UK, Chaganti RS . (1994). Allelotype analysis of cervical carcinoma. Cancer Res 54: 4481–4487.

    CAS  PubMed  Google Scholar 

  • Moch H, Presti Jr JC, Sauter G, Buchholz N, Jordan P, Mihatsch MJ et al. (1996). Genetic aberrations detected by comparative genomic hybridization are associated with clinical outcome in renal cell carcinoma. Cancer Res 56: 27–30.

    CAS  PubMed  Google Scholar 

  • Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O et al. (2007). Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356: 115–124.

    Article  CAS  PubMed  Google Scholar 

  • Nannya Y, Sanada M, Nakazaki K, Hosoya N, Wang L, Hangaishi A et al. (2005). A robust algorithm for copy number detection using high-density oligonucleotide single nucleotide polymorphism genotyping arrays. Cancer Res 65: 6071–6079.

    Article  CAS  PubMed  Google Scholar 

  • Ohba K, Miyata Y, Kanda S, Koga S, Hayashi T, Kanetake H . (2005). Expression of urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor and plasminogen activator inhibitors in patients with renal cell carcinoma: correlation with tumor associated macrophage and prognosis. J Urol 174: 461–465.

    Article  PubMed  Google Scholar 

  • Qiao Q, Ramadani M, Gansauge S, Gansauge F, Leder G, Beger HG . (2001). Reduced membranous and ectopic cytoplasmic expression of beta -catenin correlate with cyclin D1 overexpression and poor prognosis in pancreatic cancer. Int J Cancer 95: 194–197.

    Article  CAS  PubMed  Google Scholar 

  • Ried T, Knutzen R, Steinbeck R, Blegen H, Schrock E, Heselmeyer K et al. (1996). Comparative genomic hybridization reveals a specific pattern of chromosomal gains and losses during the genesis of colorectal tumors. Genes Chromosomes Cancer 15: 234–245.

    Article  CAS  PubMed  Google Scholar 

  • Shimokawa T, Furukawa Y, Sakai M, Li M, Miwa N, Lin YM et al. (2003). Involvement of the FGF18 gene in colorectal carcinogenesis, as a novel downstream target of the beta-catenin/T-cell factor complex. Cancer Res 63: 6116–6120.

    CAS  PubMed  Google Scholar 

  • Storkel S, Eble JN, Adlakha K, Amin M, Blute ML, Bostwick DG et al. (1997). Classification of renal cell carcinoma: Workgroup No. 1. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer 80: 987–989.

    Article  CAS  PubMed  Google Scholar 

  • Suzuki H, Ueda T, Komiya A, Okano T, Isaka S, Shimazaki J et al. (1997). Mutational state of von Hippel-Lindau and adenomatous polyposis coli genes in renal tumors. Oncology 54: 252–257.

    Article  CAS  PubMed  Google Scholar 

  • Swiercz R, Wolfe JD, Zaher A, Jankun J . (1998). Expression of the plasminogen activation system in kidney cancer correlates with its aggressive phenotype. Clin Cancer Res 4: 869–877.

    CAS  PubMed  Google Scholar 

  • Ueta T, Ikeguchi M, Hirooka Y, Kaibara N, Terada T . (2002). Beta-catenin and cyclin D1 expression in human hepatocellular carcinoma. Oncol Rep 9: 1197–1203.

    CAS  PubMed  Google Scholar 

  • Wagener N, Crnkovic-Mertens I, Vetter C, Macher-Goppinger S, Bedke J, Grone EF et al. (2007). Expression of inhibitor of apoptosis protein Livin in renal cell carcinoma and non-tumorous adult kidney. Br J Cancer 97: 1271–1276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang TL, Maierhofer C, Speicher MR, Lengauer C, Vogelstein B, Kinzler KW et al. (2002). Digital karyotyping. Proc Natl Acad Sci USA 99: 16156–16161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yeh SH, Chen PJ, Lai MY, Chen DS . (1996). Allelic loss on chromosomes 4q and 16q in hepatocellular carcinoma: association with elevated alpha-fetoprotein production. Gastroenterology 110: 184–192.

    Article  CAS  PubMed  Google Scholar 

  • Yoshimoto T, Matsuura K, Karnan S, Tagawa H, Nakada C, Tanigawa M et al. (2007). High-resolution analysis of DNA copy number alterations and gene expression in renal clear cell carcinoma. J Pathol 213: 392–401.

    Article  CAS  PubMed  Google Scholar 

  • Yuan D, Liu L, Gu D . (2007). Transcriptional regulation of livin by beta-catenin/TCF signaling in human lung cancer cell lines. Mol Cell Biochem 306: 171–178.

    Article  CAS  PubMed  Google Scholar 

  • Yuan E, Li CM, Yamashiro DJ, Kandel J, Thaker H, Murty VV et al. (2005). Genomic profiling maps loss of heterozygosity and defines the timing and stage dependence of epigenetic and genetic events in Wilms' tumors. Mol Cancer Res 3: 493–502.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Taeko Asano and Miyuki Katto for immunohistochemistry and microarray, respectively. We also thank Noriko Kunita for technical support. This study was performed in part as a collaborative research effort with the Clinical Informatics Research Initiative at the Organ Development Research Laboratory of the National Institute of Advanced Industrial Science and Technology (AIST), Japan.This study was supported by a grant from Scientific Research from the Japan Society for the Promotion of Science (JSPS), Japan.

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Authors and Affiliations

  1. Department of Urology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Japan

    T Kojima, T Shimazui, S Hinotsu, A Joraku, T Oikawa, K Kawai & H Akaza

  2. Department of Molecular Biological Oncology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Japan

    T Kojima, R Horie & K Uchida

  3. Research Division, MCBI, 2-10-14 Takezono, Tsukuba, Japan

    H Suzuki & R Nagashima

  4. Department of Pathology, Aichi Medical University School of Medicine, Aichi, Japan

    K Yoshikawa

  5. Organ Development Research Laboratory, National Institute of Advanced Industrial Science and Technology, 1-1-1 Higashi, Tsukuba, Japan

    T Michiue & M Asashima

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Correspondence to K Uchida.

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

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Kojima, T., Shimazui, T., Hinotsu, S. et al. Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling. Oncogene 28, 297–305 (2009). https://doi.org/10.1038/onc.2008.391

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