Merkel cell polyomavirus in colorectal cancer. Exploring the Wnt/β-catenin pathway

Merkel cell polyomavirus (MCPyV) is the established oncogenic driver of Merkel cell carcinoma (MCC), but its role in other malignancies is under investigation. Although MCPyV DNA has been detected in colorectal cancer (CRC) specimens, its biological relevance and contribution to colorectal tumorigenesis remain unclear. In this observational study, we investigated MCPyV prevalence, load and molecular status in 122 CRC specimens and peritumoral tissues. In addition, to extend beyond DNA detection, transcriptional profiling was performed to assess early (LTAg) and late (VP1) transcripts, and viral microRNAs. Furthermore, the mRNA expression levels of key Wnt signaling components, including CTNNB1, MYC and CCND1 were examined. AXIN2 was also used as a surrogate marker of pathway activation. Our findings revealed similar MCPyV prevalence and load between tumor and adjacent healthy tissues, suggesting a wide colonization of the colorectal mucosa. Sequencing analyses showed canonical NCCR and VP1 structures, and full length LTAg, with no evidence of viral integration. These data, combined with the detection of both early and late transcripts, indicate an episomal and transcriptionally active state in colorectal tissues. Notably, virus-positive tissues exhibited an over-expression of CTNNB1and its target genes across all clinical subgroups, regardless of anatomical site or tumor stage. Our results are congruent with the establishment of persistent MCPyV infection in the colorectal mucosa, potentially characterized by transcriptionally active episomal genomes. Furthermore, upregulation of the Wnt/β-catenin cascade in virus-positive tissues suggests that MCPyV may exploit this host pathway to drive cellular proliferation. A limitation of this study is lack of comparison to colorectal mucosa in patients without CRC. Overall, these findings are consistent with widespread viral colonization of the colorectal mucosa in a subset of CRC patients, and raise the hypothesis that MCPyV may modulate host signaling pathways relevant to colorectal biology. Whether MCPyV plays any etiological role in colorectal carcinogenesis, or whether its detection is coincidental, cannot be determined from the present observational data.