CD4+CD25+Foxp3+ regulatory T cells (Tregs) can inhibit cytotoxic responses. Though several studies have analyzed Treg frequency in the peripheral blood mononuclear cells (PBMCs) of pancreatic ductal adenocarcinoma (PDA) patients using flow cytometry (FCM), few studies have examined how intratumoral Tregs might contribute to immunosuppression in the tumor microenvironment. Thus, the potential role of intratumoral Tregs in PDA patients remains to be elucidated. In this study, we found that the percentages of Tregs, CD4+ T cells and CD8+ T cells were all increased significantly in tumor tissue compared to control pancreatic tissue, as assessed via FCM, whereas the percentages of these cell types in PBMCs did not differ between PDA patients and healthy volunteers. The percentages of CD8+ T cells in tumors were significantly lower than in PDA patient PBMCs. In addition, the relative numbers of CD4+CD25+Foxp3+ Tregs and CD8+ T cells were negatively correlated in the tissue of PDA patients, and the abundance of Tregs was significantly correlated with tumor differentiation. Additionally, Foxp3+ T cells were observed more frequently in juxtatumoral stroma (immediately adjacent to the tumor epithelial cells). Patients showing an increased prevalence of Foxp3+ T cells had a poorer prognosis, which was an independent factor for patient survival. These results suggest that Tregs may promote PDA progression by inhibiting the antitumor immunity of CD8+ T cells at local intratumoral sites. Moreover, a high proportion of Tregs in tumor tissues may reflect suppressed antitumor immunity.

The aberrant expression of microRNAs (miRNAs) has emerged as an important hallmark of cancer. However, the molecular mechanisms underlying the changes in miRNA expression remain unclear. In this study, we discovered a novel epigenetic mechanism of miR-506 regulation and investigated its functional significance in pancreatic cancer. Sequencing analysis revealed that the miR-506 promoter is highly methylated in pancreatic cancer tissues compared with non-cancerous tissues. Reduced miR-506 expression was significantly associated with clinical stage, pathologic tumor status, distant metastasis and decreased survival of pancreatic cancer patients. miR-506 inhibited cell proliferation, induced cell cycle arrest at the G1/S transition and enhanced apoptosis and chemosensitivity of pancreatic cancer cells. Furthermore, we identified sphingosine kinase 1 (SPHK1) as a novel target of miR-506, the expression of which inhibited the SPHK1/Akt/NF-κB signaling pathway, which is activated in pancreatic cancer. High SPHK1 expression was significantly associated with poor survival in a large cohort of pancreatic cancer specimens. Our data suggest that miR-506 acts as a tumor suppressor miRNA and is epigenetically silenced in pancreatic cancer. The newly identified miR-506/SPHK1 axis represents a novel therapeutic strategy for future pancreatic cancer treatment.

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Pancreatic cancer remains one of the most malignant tumors with a poor prognosis. Despite advances in diagnosis and treatment, no reliable biomarkers are available for clinical practice. Circular RNAs (circRNAs) are a novel class of endogenous non-coding RNA, which are abundant, stable and conserved, and serve crucial roles in disease, particularly in cancer. The purpose of the present study was to investigate the expression profile of circRNAs in 20 pancreatic cancer tissues and corresponding paracancerous tissues using arraystar human circRNA array analysis, high-throughput circRNA microarray, bioinformatic analysis and reverse transcription-quantitative polymerase chain reaction. It was revealed that the circRNAs expression profile was significantly different between pancreatic cancer tissue and paracancerous tissue, which indicates a potential role in pancreatic cancer. It was predicted that circRNAs may act as a micro RNA sponge to modulate gene expression in pancreatic cancer. Additionally, microarray expression analysis data was submitted to the Gene Expression Omnibus under accession no. GSE79634. The present study revealed that circRNAs expression was visibly diverse in pancreatic cancer compared with paracancerous tissue and provides more reliable biomarkers and new insights into the mechanisms of pancreatic cancer.