Abstract
Pancreatic ductal adenocarcinoma (PDAC), which accounts for 96% of all pancreatic cancer cases, is characterized by rapid progression, invasion and metastasis. Transforming growth factor-beta (TGF-β) signaling is an essential pathway in metastatic progression and microRNAs (miRNA) play central roles in the regulation of various biological and pathologic processes including cancer metastasis. However, the molecular mechanisms involved in regulation of miRNAs and activation of TGF-β signaling in PDAC remain to be established. The results of this study suggested that miR-323-3p expression in PDAC tissues and cell lines was significantly decreased compared to levels in normal pancreatic tissues and primary cultured pancreatic duct epithelial cells. Further investigation revealed that miR-323-3p directly targeted and suppressed SMAD2 and SMAD3, both key components in TGF-β signaling. Lower levels of miR-323-3p predicted poorer prognosis in patients with PDAC. Ectopic overexpression of miR-323-3p significantly inhibited, while silencing of miR-323-3p increased the migration and invasion abilities of PDAC cells in vitro. Moreover, using an in vivo mouse model, we demonstrated that overexpressing of miR-323-3p significantly reduced, while knockdown of miR-323-3p enhanced lung metastatic colonization of PANC-1 cells. Furthermore, miR-323-3p-induced TGF-b signaling inhibition and cell motility suppression were partially rescued by overexpressing of Smad2 and Smad3 in PDAC cells. Our findings suggest that re-expression of miR-323-3p might offer a novel therapeutic target against metastasis in patients with PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC), which accounts for 96% of all pancreatic cancer cases, is the fourth leading cause of cancer related death in developed countries [1]
We found that miR-323-3p was significantly decreased in PDAC cells compared to normal pancreatic cells, and that downregulation of miR-323-3p promoted invasion and metastatic colonization of the lung
In order to identify miRNAs involved in the regulation of PDAC progression, miRNA expression profiles were analysed in The Cancer Genome Atlas (TCGA) microarray and GEO datasets
Summary
Pancreatic ductal adenocarcinoma (PDAC), which accounts for 96% of all pancreatic cancer cases, is the fourth leading cause of cancer related death in developed countries [1]. The high mortality rate is primarily due to the high frequency of metastatic disease; over 80% of patients diagnosed with PDAC present too late for curative treatment due to metastasis [2, 3]. The underlying mechanisms concerning cancer metastasis remains to be fully elucidated and is essential to develop anti-metastatic strategies in the future [4]. Transforming growth factor-beta (TGF-β) signaling plays central roles in multiple biological processes, including embryonic development and cancer progression www.impactjournals.com/oncotarget [5, 6]. The TGF-β-SMAD pathway promotes cancer progression by regulating multiple stages in the metastatic process, including epithelial-to-mesenchymal transition (EMT). Overactive TGF-β-SMAD2 signaling has been reported to maintain epigenetic silencing of E-cadherin via regulation of DNA methylation [18]
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