Low miR200c expression in tumor budding of invasive front predicts worse survival in patients with localized colon cancer and is related to PD-L1 overexpression

At the histological level, tumor budding in colon cancer is the result of cells undergoing at least partial epithelial-to-mesenchymal transition. The microRNA 200 family is an important epigenetic driver of this process, mainly by downregulating zinc-finger E-box binding homeobox (ZEB) and transforming growth factor beta (TGF-beta) expression. We retrospectively explored the expression of the miR200 family, and ZEB1 and ZEB2, and their relationship with immune resistance mediated through PD-L1 overexpression. For this purpose, we analyzed a series of 125 colon cancer cases and took samples from two different tumor sites: the area of tumor budding at the invasive front and from the tumor center. We found significant ZEB overexpression and a reduction in miR200 in budding areas, a profile compatible with epithelial-to-mesenchymal transition. In multivariate analysis of the cases with localized disease, low miR200c expression in budding areas, but not at the tumor center, was an adverse tumor-specific survival factor (hazard ratio: 0.12; 95% confidence interval: 0.03-0.81; p = 0.02) independent of the clinical stage of the disease. PD-L1 was significantly overexpressed in the budding areas and its levels correlated with a mesenchymal transition profile. These results highlight the importance of including budding areas among the samples used for biomarker evaluation and provides relevant data on the influence of mesenchymal transition in the immune resistance mediated by PD-L1 overexpression.