MiR-200c-3p Modulates Cisplatin Resistance in Biliary Tract Cancer by ZEB1-Independent Mechanisms

SIMPLE SUMMARY: Biliary tract cancer is a rare malignancy with poor overall survival. The majority of patients are faced with advanced disease stage. Cisplatin-based treatment schedules represent the mainstay of first-line therapeutic strategy, yet only a small portion of patients develop a treatment response. One of the main reasons is acquired drug resistance. Previous studies correlated certain microRNAs (miRNAs), including miR-200c-3p, with drug resistance in various cancer types. However, limited knowledge exists about miR-200c-3p expression and cisplatin resistance in biliary tract cancer. Thus, the main aim of this study was to investigate the influence of miR-200c-3p on the cisplatin resistance in this cancer entity. We demonstrated that miR-200c-3p contributes to cisplatin resistance independently of its known influence on ZEB1 expression. ABSTRACT: Biliary tract cancer is a major global health issue in cancer-related mortality. Therapeutic options are limited, and cisplatin-based treatment schedules represent the mainstay of first-line therapeutic strategies. Although the gain of survival by the addition of cisplatin to gemcitabine is moderate, acquired cisplatin resistance frequently leads to treatment failures with mechanisms that are still poorly understood. Epithelial–mesenchymal transition (EMT) is a dynamic process that changes the shape, function, and gene expression pattern of biliary tract cancer cells. In this study, we explored the influence of the EMT-regulating miR-200c-3p on cisplatin sensitivity in biliary tract cancer cells. Using gain of function experiments, we demonstrated that miR-200c-3p regulates epithelial cell markers through the downregulation of the transcription factor ZEB1. MiR-200c-3p upregulation led to a decreased sensitivity against cisplatin, as observed in transient overexpression models as well as in cell lines stably overexpressing miR-200c-3p. The underlying mechanism seems to be independent of miR-200c-3p’s influence on ZEB1 expression, as ZEB1 knockdown resulted in the opposite effect on cisplatin resistance, which was abolished when ZEB1 knockdown and miR-200c-3p overexpression occurred in parallel. Using a gene panel of 40 genes that were previously associated with cisplatin resistance, two (Dual Specificity Phosphatase 16 (DUSP16) and Stratifin (SFN)) were identified as significantly (>2 fold, p-value < 0.05) up-regulated in miR-200c-3p overexpressing cells. In conclusion, miR-200c-3p might be an important contributor to cisplatin resistance in biliary tract cancer, independently of its interaction with ZEB1.