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

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 BRAF V600E mutation due to promoter methylation as reported previously. Importantly, we find MCC interacts with b-catenin and that reexpression of MCC in CRC cells specifically inhibits Wnt signaling, b-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, b-catenininteracting protein that can act as a potential tumor suppressor in the serrated CRC pathway by inhibiting Wnt/b-catenin signal transduction.

Distinct WNT/β-catenin signaling activation in the serrated neoplasia pathway and the adenoma-carcinoma sequence of the colorectum

“…In immunohistochemical studies, strong APC expression was observed in most SSA/Ps, whereas MCC expression was reported to be frequently lost. 21,22 MCC methylation is more common in SSA/Ps (89%) than in adenomas (35%). 20 Our study showed that MCC was methylated in 15% of SSA/Ps, and in all of SSA/Ps with high-grade dysplasia and those with submucosal carcinoma, but only 11-16% of the adenoma series.…”

“…As a result, free b-catenin accumulates and translocates into the nucleus and subsequently binds to the T-cell factor/ lymphoid enhancer factor initiating transcription of target genes such as c-myc. 17 b-Catenin is also regulated by various other components such as mutated in colorectal cancer (MCC) and secreted frizzled-related proteins (SFRPs); 17 the functions of MCC or SFRPs as negative regulators of WNT/b-catenin signaling may have important implications in genesis of colorectal carcinomas [19][20][21] as well as SSA/P. 22 AXIN2 has been found to be silenced, apparently as a result of methylation of its promoter region, specifically in colorectal carcinomas with high levels of microsatellite instability.…”

The PDZ domain protein Mcc is a novel effector of non-canonical Wnt signaling during convergence and extension in zebrafish

“…In overexpression studies, MCC was shown to physically associate with β-catenin in the nucleus to negatively regulate canonical TCF/ LEF-dependent Wnt signaling and to inhibit cell proliferation (Fukuyama et al, 2008;Matsumine et al, 1996). More recently, MCC was observed to be mainly localized in the cytoplasm of colon cancer cell lines but translocated to the nucleus in response to DNA damage to induce cell cycle arrest (Pangon et al, 2010).…”

“…MCC has previously been reported to antagonize canonical Wnt signaling in CRC cell lines (Fukuyama et al, 2008). We evaluated whether Mcc can inhibit β-catenin-dependent activation of the −0.8 kb Xenopus Siamois luciferase reporter, and found that Mcc overexpression has no effect on reporter activation -neither synergy nor inhibition -upon co-injection of mRNA encoding either the canonical Wnt8 ligand, which normally suppresses dorsal organizer genes and patterns ventrolateral mesoderm, or its effector β-catenin (Baker et al, 2010) (supplementary material Fig.…”

“…Immunolocalization studies in a variety of cell types show that MCC is principally a cytoplasmic protein (Fukuyama et al, 2008;Matsumine et al, 1996;Pangon et al, 2010;Senda et al, 1999). We determined the subcellular distribution of Mcc in the gastrulating zebrafish embryo by injecting mRNA encoding an N-terminal GFP-Mcc fusion protein and imaging GFP fluorescence at shield stage.…”