Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive carcinoma entities worldwide with early and rapid dissemination. Recently, we discussed the role of microRNAs as epigenetic regulators of Epithelial-to-Mesenchymal Transition (EMT) in PDAC. In this study, we investigated their value as diagnostic and prognostic markers in tissue and blood samples of 185 patients including PDAC, non-malignant pancreatic disorders, and age-matched healthy controls. Expression of the microRNA-200-family (microRNAs -141, -200a, -200b, -200c, -429) and microRNA-148a was significantly downregulated in tissue of PDAC Union internationale contre le cancer (UICC) Stage II. Correspondingly, stromal PDAC tissue showed strong expression of Fibronectin, Vimentin, and ZEB-1 (Zinc finger E-box-binding homeobox) versus low expression of E-cadherin. Transient transfection of microRNA-200b and microRNA-200c mimics resulted in the downregulation of their key target ZEB-1. Inversely, blood serum analyses of patients with PDAC UICC Stages II, III, and IV showed a significant over-expression of microRNA-200-family members, microRNA-148a, microRNA-10b, and microRNA-34a. Correspondingly, Enzyme-linked Immunosorbent Assay (ELISA) analyses revealed a significant over-expression of soluble E-cadherin in serum samples of PDAC patients versus healthy controls. The best diagnostic accuracy to distinguish between PDAC and non-PDAC in this patient collective could be achieved in tissue by microRNA-148a with an area under the receiver-operating-characteristic (ROC) curve (AUC) of 0.885 and in blood serum by a panel of microRNA-141, -200b, -200c, and CA.19-9 with an AUC of 0.890. Both diagnostic tools outreach the diagnostic performance of the currently most common diagnostic biomarker CA.19-9 (AUC of 0.834). Kaplan Meier survival analysis of this patient collective revealed an improved overall survival in PDAC patients with high expression of tissue-related microRNA-34a, -141, -200b, -200c, and -429. In conclusion, EMT-regulating microRNAs have great potential as liquid and solid biopsy markers in PDAC patients. Their prognostic and therapeutic benefits remain important tasks for future studies.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal tumors worldwide with locoregional spread and distant metastasis in about 80%
Upregulated microRNA-200b and microRNA-200c by transient transfection with mimics resulted in the downregulation of their key target protein, the transcription factor ZEB-1, in the mesenchymal PDAC cell line Mia-PaCa-2 (Figure 1C)
A plethora of preclinical studies could demonstrate that Epithelial-to-Mesenchymal Transition (EMT) is a process closely associated with tumor progression, metastasis, and prognosis in gastrointestinal gastrointestinal cancer cancer including including PDAC
Summary
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal tumors worldwide with locoregional spread and distant metastasis in about 80%. Rapid disease progression and early metastasis lead to late diagnosis at advanced unresectable stages with an overall cumulative 5-year survival rate below 1% [1,2]. Transition (EMT) plays a crucial role in the invasion and metastasis of diverse carcinomas, including. EMT is characterized by a loss of epithelial cell-to-cell contacts and by epithelial cells acquiring motile mesenchymal features leading to cell migration and invasion. At the site of metastases the disseminated mesenchymal tumor cells undergo the reverse transition as Mesenchymal-to-Epithelial Transition (MET) [4–7]. Metastasis is a complex multistep biological process that is controlled by distinct genes and signaling pathways including EMT-promoting
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