Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by fast tumor progression and diagnosis at advanced, inoperable stages. Previous studies could demonstrate an involvement of miR-192-5p in epigenetic regulation of visceral carcinomas. Due to contradictory results, however, the clinical utility of miR-192-5p in PDAC has yet to be determined. MiR-192-5p expression was analyzed by RT-qRT-PCR in human PDAC and benign tissue (n = 78), blood serum (n = 81) and serum exosomes (n = 74), as well as in PDAC cell lines (n = 5), chemoresistant cell clones (n = 2), and pancreatic duct cell line H6c7. Analysis of EMT-associated (epithelial-to-mesenchymal transition) proteins was performed by immunohistochemistry and Western blot. MiR-192-5p was deregulated in PDAC as compared to healthy controls (HCs), with downregulation in macrodissected tissue (p < 0.001) and upregulation in blood serum of PDAC UICC (Union for International Cancer Control) stage IV (p = 0.016) and serum exosomes of PDAC UICC stages II to IV (p < 0.001). MiR-192-5p expression in tumor tissue was significantly lower as compared to corresponding peritumoral tissue (PDAC UICC stage II: p < 0.001; PDAC UICC stage III: p = 0.024), while EMT markers ZEB1 and ZEB2 were more frequently expressed in tumor tissue as compared to peritumoral tissue, HCs, and chronic pancreatitis. Tissue-derived (AUC of 0.86; p < 0.0001) and exosomal (AUC of 0.83; p = 0.0004) miR-192-5p could differentiate between PDAC and HCs with good accuracy. Furthermore, high expression of miR-192-5p in PDAC tissue of curatively resected PDAC patients correlated with prolonged overall and recurrence-free survival in multivariate analysis. In vitro, miR-192-5p was downregulated in gemcitabine-resistant cell clones of AsPC-1 (p = 0.029). Transient transfection of MIA PaCa-2 cells with miR-192-5p mimic resulted in downregulation of ZEB2. MiR-192-5p seems to possess a tumor-suppressive role and high potential as a diagnostic and prognostic marker in PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) remains to be one of the most lethal malignant diseases in western countries
In PDAC, we have recently reported on the tumor suppressive role of the miR-200-family as inhibitors of EMT, a vital process preceding metastatic dissemination [13,14]
Metastasized PDAC cells derived from malignant ascites, presented with a significant overexpression of
Summary
Pancreatic ductal adenocarcinoma (PDAC) remains to be one of the most lethal malignant diseases in western countries. The five-year relative survival rate of PDAC is less than 10% and this is mainly attributed to its high invasiveness and fast tumor progression [1,2]. As a result of innovative diagnostic tools, pharmaceuticals, and surgical techniques, considerable advances have been achieved in the management of multiples types of cancer. Therapy of PDAC is interdisciplinary and multimodal, while surgical resection currently represents the only treatment option potentially enabling long-term survival. Due to a lack of disease-specific symptoms, diagnosis of early-stage PDAC is often incidental and patients usually present with advanced, inoperable disease, leaving no possibility for curation. Gemcitabine and FOLFIRINOX (folinic acid, fluorouracil, irinotecan, oxaliplatin) are commonly administered chemotherapeutic regimens in the adjuvant and palliative management of PDAC and have been shown to slightly improve the prognostic outcome of patients. Response rates to chemotherapy are reported to be as low as 9.4–31.6% in the metastatic setting, yet another reason for the fatal prognosis of the disease [3,4,5]
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