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Mutated in colorectal cancer, a putative tumor suppressor for serrated colorectal cancer, selectively represses β-catenin-dependent transcription

Oncogene volume 27, pages 6044–6055 (2008)Cite this article

Abstract

Mutated in colorectal cancer (MCC) was originally identified as a candidate gene for familial adenomatous polyposis (FAP) but further study identified adenomatous polyposis coli (APC) as responsible for FAP and the physiologic/pathologic roles of MCC remained poorly understood. Recently, MCC promoter methylation was discovered as a frequent early event in a distinct subset of precursor lesions and colorectal cancer (CRC) associated with the serrated CRC pathway. Here we provide the first evidence of the biological significance of MCC loss in CRC and the molecular pathways involved. We show MCC expression is dramatically decreased in many CRC cell lines and the distinct subset of sporadic CRC characterized by the CpG island methylator phenotype and BRAFV600E mutation due to promoter methylation as reported previously. Importantly, we find MCC interacts with β-catenin and that reexpression of MCC in CRC cells specifically inhibits Wnt signaling, β-catenin/T-cell factor/lymphoid-enhancer factor-dependent transcription and cellular proliferation even in the presence of oncogenic mutant APC. We also show that MCC is localized in the nucleus and identify two functional nuclear localization signals. Taken together, MCC is a nuclear, β-catenin-interacting protein that can act as a potential tumor suppressor in the serrated CRC pathway by inhibiting Wnt/β-catenin signal transduction.

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References

  • Agarwal A, Das K, Lerner N, Sathe S, Cicek M, Casey G et al. (2005). The AKT/I kappa B kinase pathway promotes angiogenic/metastatic gene expression in colorectal cancer by activating nuclear factor-kappa B and beta-catenin. Oncogene 24: 1021–1031.

    Article  CAS  PubMed  Google Scholar 

  • Ashton-Rickardt PG, Wyllie AH, Bird CC, Dunlop MG, Steel CM, Morris RG et al. (1991). MCC, a candidate familial polyposis gene in 5q.21, shows frequent allele loss in colorectal and lung cancer. Oncogene 6: 1881–1886.

    CAS  PubMed  Google Scholar 

  • Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K et al. (2004). A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nat Cell Biol 6: 97–105.

    Article  CAS  PubMed  Google Scholar 

  • Conacci-Sorrell M, Simcha I, Ben-Yedidia T, Blechman J, Savagner P, Ben-Ze'ev A . (2003). Autoregulation of E-cadherin expression by cadherin-cadherin interactions: the roles of beta-catenin signaling, Slug, and MAPK. J Cell Biol 163: 847–857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eleftheriou A, Yoshida M, Henderson BR . (2001). Nuclear export of human beta-catenin can occur independent of CRM1 and the adenomatous polyposis coli tumor suppressor. J Biol Chem 276: 25883–25888.

    Article  CAS  PubMed  Google Scholar 

  • Fukuyama R, Ng KP, Cicek M, Kelleher C, Niculaita R, Casey G et al. (2006). Role of IKK and oscillatory NFkappaB kinetics in MMP-9 gene expression and chemoresistance to 5-fluorouracil in RKO colorectal cancer cells. Mol Carcinog 46: 402–413.

    Article  Google Scholar 

  • Gregorieff A, Clevers H . (2005). Wnt signaling in the intestinal epithelium: from endoderm to cancer. Genes Dev 19: 877–890.

    Article  CAS  PubMed  Google Scholar 

  • Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ et al. (2004). IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118: 285–296.

    Article  CAS  PubMed  Google Scholar 

  • Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen H et al. (1991). Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66: 589–600.

    CAS  PubMed  Google Scholar 

  • Henderson BR . (2000). Nuclear-cytoplasmic shuttling of APC regulates beta-catenin subcellular localization and turnover. Nat Cell Biol 2: 653–660.

    Article  CAS  PubMed  Google Scholar 

  • Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB . (1996). Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 93: 9821–9826.

    Article  CAS  PubMed  Google Scholar 

  • Heyer J, Yang K, Lipkin M, Edelmann W, Kucherlapati R . (1999). Mouse models for colorectal cancer. Oncogene 18: 5325–5333.

    Article  CAS  PubMed  Google Scholar 

  • Ishikawa S, Kobayashi I, Hamada J, Tada M, Hirai A, Furuuchi K et al. (2001). Interaction of MCC2, a novel homologue of MCC tumor suppressor, with PDZ-domain protein AIE-75. Gene 267: 101–110.

    Article  CAS  PubMed  Google Scholar 

  • Ishitani T, Ninomiya-Tsuji J, Matsumoto K . (2003). Regulation of lymphoid enhancer factor 1/T-cell factor by mitogen-activated protein kinase-related Nemo-like kinase-dependent phosphorylation in Wnt/beta-catenin signaling. Mol Cell Biol 23: 1379–1389.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ishitani T, Ninomiya-Tsuji J, Nagai S, Nishita M, Meneghini M, Barker N et al. (1999). The TAK1-NLK-MAPK-related pathway antagonizes signalling between beta-catenin and transcription factor TCF. Nature 399: 798–802.

    Article  CAS  PubMed  Google Scholar 

  • Jass JR . (2005). Serrated adenoma of the colorectum and the DNA-methylator phenotype. Nat Clin Pract Oncol 2: 398–405.

    Article  CAS  PubMed  Google Scholar 

  • Jass JR . (2007). Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 50: 113–130.

    Article  CAS  PubMed  Google Scholar 

  • Jass JR, Barker M, Fraser L, Walsh MD, Whitehall VL, Gabrielli B et al. (2003). APC mutation and tumour budding in colorectal cancer. J Clin Pathol 56: 69–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jass JR, Whitehall VL, Young J, Leggett BA . (2002). Emerging concepts in colorectal neoplasia. Gastroenterology 123: 862–876.

    Article  CAS  PubMed  Google Scholar 

  • Kinzler KW, Nilbert MC, Su LK, Vogelstein B, Bryan TM, Levy DB et al. (1991a). Identification of FAP locus genes from chromosome 5q21. Science 253: 661–665.

    Article  CAS  PubMed  Google Scholar 

  • Kinzler KW, Nilbert MC, Vogelstein B, Bryan TM, Levy DB, Smith KJ et al. (1991b). Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science 251: 1366–1370.

    Article  CAS  PubMed  Google Scholar 

  • Kohonen-Corish MR, Sigglekow ND, Susanto J, Chapuis PH, Bokey EL, Dent OF et al. (2007). Promoter methylation of the mutated in colorectal cancer gene is a frequent early event in colorectal cancer. Oncogene 26: 4435–4441.

    Article  CAS  PubMed  Google Scholar 

  • Lindor NM, Smalley R, Barker M, Bigler J, Krumroy LM, Lum-Jones A et al. (2006). Ascending the learning curve—MSI testing experience of a six-laboratory consortium. Cancer Biomarkers 2: 5–9.

    Article  CAS  PubMed  Google Scholar 

  • Luo JL, Maeda S, Hsu LC, Yagita H, Karin M . (2004). Inhibition of NF-kappaB in cancer cells converts inflammation- induced tumor growth mediated by TNFalpha to TRAIL-mediated tumor regression. Cancer Cell 6: 297–305.

    Article  CAS  PubMed  Google Scholar 

  • Matsumine A, Senda T, Baeg GH, Roy BC, Nakamura Y, Noda M et al. (1996). MCC, a cytoplasmic protein that blocks cell cycle progression from the G0/G1 to S phase. J Biol Chem 271: 10341–10346.

    Article  CAS  PubMed  Google Scholar 

  • Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H, Horii A et al. (1991). Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253: 665–669.

    Article  CAS  PubMed  Google Scholar 

  • Nourry C, Grant SG, Borg JP . (2003). PDZ domain proteins: plug and play! Sci STKE. http://stke.sciencemag.org/cgi/content/full/sigtrans;2003/179/re7.

  • Ogino S, Kawasaki T, Kirkner GJ, Loda M, Fuchs CS . (2006). CpG island methylator phenotype-low (CIMP-low) in colorectal cancer: possible associations with male sex and KRAS mutations. J Mol Diagn 8: 582–588.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prall F, Ostwald C . (2007). High-degree tumor budding and podia-formation in sporadic colorectal carcinomas with K-ras gene mutations. Hum Pathol 38: 1696–1702.

    Article  CAS  PubMed  Google Scholar 

  • Rosin-Arbesfeld R, Townsley F, Bienz M . (2000). The APC tumour suppressor has a nuclear export function. Nature 406: 1009–1012.

    Article  CAS  PubMed  Google Scholar 

  • Senda T, Matsumine A, Yanai H, Akiyama T . (1999). Localization of MCC (mutated in colorectal cancer) in various tissues of mice and its involvement in cell differentiation. J Histochem Cytochem 47: 1149–1158.

    Article  CAS  PubMed  Google Scholar 

  • Shinto E, Tsuda H, Ueno H, Hashiguchi Y, Hase K, Tamai S et al. (2005). Prognostic implication of laminin-5 gamma 2 chain expression in the invasive front of colorectal cancers, disclosed by area-specific four-point tissue microarrays. Lab Invest 85: 257–266.

    Article  CAS  PubMed  Google Scholar 

  • Sizemore N, Lerner N, Dombrowski N, Sakurai H, Stark GR . (2002). Distinct roles of the Ikappa B kinase alpha and beta subunits in liberating nuclear factor kappa B (NF-kappa B) from Ikappa B and in phosphorylating the p65 subunit of NF-kappa B. J Biol Chem 277: 3863–3869.

    Article  CAS  PubMed  Google Scholar 

  • Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA et al. (2006). CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 38: 787–793.

    Article  CAS  PubMed  Google Scholar 

  • Zhang F, White RL, Neufeld KL . (2000). Phosphorylation near nuclear localization signal regulates nuclear import of adenomatous polyposis coli protein. Proc Natl Acad Sci USA 97: 12577–12582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zlobec I, Lugli A, Baker K, Roth S, Minoo P, Hayashi S et al. (2007). Role of APAF-1, E-cadherin and peritumoral lymphocytic infiltration in tumour budding in colorectal cancer. J Pathol 212: 260–268.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr Kenneth W Kinzler, Dr Kazuo Maruyama, Dr Inder Verma, Dr Bert Vogelstein and Dr Bryan Williams for the various reagents used for this work as well as Lisa Krumroy and Alona Merkulova for technical assistance. This work was supported by grants to NS from the Cleveland Clinic Taussig Cancer Center/Scott Hamilton CARES Initiative and the National Cancer Institute Grant CA 100748.

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Author notes

  1. R Fukuyama

    Present address: 5Current address: Aichi Cancer Center, Nagoya 464-8682, Japan.,

  2. K P Ng

    Present address: 6Current address: Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA.,

Authors and Affiliations

  1. Department of Cancer Biology, Cleveland Clinic, Cleveland, OH, USA

    R Fukuyama, R Niculaita, K P Ng, P P Aung, G Casey & N Sizemore

  2. School of Biomedical Sciences, Kent State University, Kent, OH, USA

    R Niculaita & N Sizemore

  3. Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA

    E Obusez, G Casey & N Sizemore

  4. Department of Colorectal Surgery, Cleveland Clinic, Cleveland, OH, USA

    J Sanchez, M Kalady, G Casey & N Sizemore

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Correspondence to N Sizemore.

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

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Fukuyama, R., Niculaita, R., Ng, K. et al. Mutated in colorectal cancer, a putative tumor suppressor for serrated colorectal cancer, selectively represses β-catenin-dependent transcription. Oncogene 27, 6044–6055 (2008). https://doi.org/10.1038/onc.2008.204

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