Epigenetic Biomarkers and the Wnt/β-Catenin Pathway in Opisthorchis viverrini-associated Cholangiocarcinoma: A Scoping Review on Therapeutic Opportunities.

Background: Epigenetic modifications, such as DNA methylation and histone modifications, are pivotal in regulating gene expression pathways related to inflammation and cancer. While there is substantial research on epigenetic marks in cholangiocarcinoma (CCA), Opisthorchis viverrini-induced cholangiocarcinoma (Ov-CCA) is overlooked as a neglected tropical disease (NTD) with limited representation in the literature. Considering the distinct etiological agent, pathogenic mechanisms, and pathological manifestations, epigenetic research plays a pivotal role in uncovering markers and potential targets related to the cancer-promoting and morbidity-inducing liver fluke parasite prevalent in the Great Mekong Subregion (GMS). Emerging studies highlight a predominant hypermethylation phenotype in Opisthorchis viverrini (O. viverrini) tumor tissues, underscoring the significance of abnormal DNA methylation and histone modifications in genes and their promoters as reliable targets for Ov-CCA. Principal findings: Relevant published literature was identified by searching major electronic databases using targeted search queries. This process retrieved a total of 81 peer-reviewed research articles deemed eligible for inclusion, as they partially or fully met the pre-defined selection criteria. These eligible articles underwent a qualitative synthesis and were included in the systematic review. Within these, 11 studies specifically explored Ov-CCA tissues to investigate potential epigenetic biomarkers and therapeutic targets. This subset of 11 articles provided a foundation for exploring the applications of epigenetics-based therapies and biomarkers for Ov-CCA. These articles delved into various epigenetic modifications, including DNA methylation and histone modifications, and examined genes with aberrant epigenetic changes linked to deregulated signalling pathways in Ov-CCA progression. Conclusions: This review identified epigenetic changes and Wnt/β-catenin pathway deregulation as key drivers in Ov-CCA pathogenesis. Promoter hypermethylation of specific genes suggests potential diagnostic biomarkers and dysregulation of Wnt/β-catenin-modulating genes contributes to pathway activation in Ov-CCA progression. Reversible epigenetic changes offer opportunities for dynamic disease monitoring and targeted interventions. Therefore, this study underscores the importance of these epigenetic modifications in Ov-CCA development, suggesting novel therapeutic targets within disrupted signalling networks. However, additional validation is crucial for translating these novel insights into clinically applicable strategies, enhancing personalised Ov-CCA management approaches. Author summary: This review examines the role of epigenetic changes and the Wnt/β-catenin signalling pathway in Opisthorchis viverrini-induced cholangiocarcinoma (Ov-CCA). Through an exhaustive analysis of relevant studies, the primary epigenetic alteration identified in Ov-CCA pathogenesis is hypermethylation of tumor suppressor gene promoters. This epigenetic dysregulation shows several affected genes involved in the Wnt/β-catenin signalling pathway, which plays a central role in opisthorchiasis progression. Network analysis revealed an interaction between these genes and β-catenin, suggesting Wnt/β-catenin pathway dysregulation contributes to Ov-CCA development and progression. Most methylated genes act as tumor suppressors by normally inhibiting the Wnt/β-catenin pathway. Targeting this pathway offers therapeutic potential for Ov-CCA. Epigenetic markers hold promise as biomarkers, emphasizing the therapeutic potential of targeting disrupted gene and signalling networks through epigenetic modulators. This approach presents an innovative strategy for developing personalized therapies tailored to the molecular profiles of Ov-CCA patients. However, translating these findings into clinical practice requires rigorous validation and further in-depth exploration. Nonetheless, the insights obtained highlight the crucial necessity for ongoing research on epigenetic-based interventions, intending to enhance both diagnostic accuracy and therapeutic effectiveness in managing Ov-CCA. [ABSTRACT FROM AUTHOR]