Abstract
MicroRNAs can function as key tumor suppressors or oncogenes and act as biomarkers for cancer diagnosis or prognosis. Although high-throughput assays have revealed many miRNA biomarkers for pancreatic ductal adenocarcinoma (PDAC), only a few have been validated in independent populations or investigated for functional significance in PDAC pathogenesis. In this study, we correlated the expression of 36 potentially prognostic miRNAs within PDAC tissue with clinico-pathological features and survival in 151 Chinese patients. We then analyzed the functional roles and target genes of two miRNAs in PDAC development. We found that high expression of miR-186 and miR-326 predict poor and improved survival, respectively. miR-186 was over-expressed in PDAC patients compared with controls, especially in patients with large tumors (>2 cm), lymph node metastasis, or short-term survival (< 24 months). In contrast, miR-326 was down-regulated in patients compared with controls and displayed relatively increased expression in the patients with long-term survival or without venous invasion. Functional experiments revealed that PDAC cell proliferation and migration was decreased following inhibition and enhanced following over-expression of miR-186. In contrast, it was enhanced following inhibition and decreased after over-expression of miR-326. A luciferase assay indicated that miR-186 can bind directly to the 3′-UTR of NR5A2 to repress gene expression. These findings suggest that miR-186 over-expression contributes to the invasive potential of PDAC, likely via suppression of NR5A2, thereby leading to a poor prognosis; high miR-326 expression prolongs survival likely via the decreasing invasive potential of PDAC cells. These two miRNAs can be used as markers for clinical diagnosis and prognosis, and they represent therapeutic targets for PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the industrialized world and sixth in China [1,2]
We found that several miRNAs exhibited significant associations with tumor size, lymph node metastasis, venous invasion, and survival time. miR-186 and 326 inspired further research as they consistently predicted multiple clinic-pathological features and survival with the most significant levels among identified miRNAs
Because little is known about the roles of these two miRNAs in carcinogenesis of pancreatic ductal adenocarcinoma (PDAC), we subsequently investigated their function in PDAC cell proliferation and migration and sought to identify their specific target mRNAs
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the industrialized world and sixth in China [1,2]. Improving the PC mortality rate necessitates the discovery of new tools for the early detection, diagnosis, and monitoring of therapeutic efficacy. Decades of studies revealed that persistent alterations in gene expression patterns due to epigenetic modifications, gene mutations and deletions are crucial for the development, progression, and maintenance of pancreatic tumors [4]. Numerous changes in gene expression have been found in PDAC, it has been a challenge to identify the key genes that are responsible for the carcinogenesis and progression of pancreatic cancer. A gene that significantly predicts cancer progression and prognosis may directly participate in carcinogenesis or interact with a gene that acts in the pathogenesis of cancer [5]. Identifying novel markers is helpful for developing new methods of early diagnosis and improving the dismal prognosis [6]
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