Expression Levels of microRNAs miR-93 and miR-200a in Pancreatic Adenocarcinoma with Special Reference to Differentiation and Relapse-Free Survival

Abstract

Objectives: Protein levels of the transcription factor nuclear factor erythroid-derived 2-like 2 (Nrf2) and its inhibitor Kelch-like ECH-associated protein 1 (Keap1) have been proposed as prognostic factors in pancreatic ductal adenocarcinomas (PDACs). These cellular redox-state-regulating enzymes are targeted by several microRNAs, including miR-93 and miR-200a. Methods: We assessed mRNA levels of Nrf2 and Keap1 and tissue expression of miR-93 and miR-200a in 51 patients with surgically treated PDAC. Expression levels were separately measured in malignant cells and adjacent benign cells. Results: Keap1 and Nrf2 mRNA expression levels in cancer cells were lower than in adjacent benign tissue (Wilcoxon’s test; p = 0.0015 and p = 0.000032, respectively). Conversely, miR-93 expression was higher in cancer cells than in adjacent benign tissue (p = 0.00082). Low levels of miR-93 and miR-200a in cancer cells were associated with poorer differentiation (p = 0.004 and p = 0.002, respectively). In univariate survival analysis, benign-tissue levels of miR-200a above the median predicted better relapse-free survival (RFS) (p = 0.045). Conclusions: High miR-93 and miR-200a levels in cancer cells of PDAC were associated with better differentiation, and miR-200a expression in benign tissue with excellent RFS. Keap1 and Nrf2 mRNA levels showed prominent down-regulation in cancerous versus benign tissue, but they were not associated with disease aggressiveness or outcome.