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.

The inhibitor effect of estrogen on osteoclasts differentiation is very important in the etiology of estrogen protecting the adult skeleton against bone loss. However, the precise molecular events underlying the effect of estrogen on osteoclasts differentiation are not known. Recent studies implicated an important role of transient receptor potential vanilloid 5 (TRPV5) in osteoclast differentiation and bone resorption. Furthermore, some studies have confirmed that estrogen is involved in the regulation of calcium ion (Ca(2+)) influx in many cells via TRPV5 channel. Therefore, we hypothesize that TRPV5 channel may be implicated in the process of estrogen-inhibited osteoclastogenesis and bone resorption. Western blot, quantitative real-time PCR, tartrate-resistant acid phosphatase (TRAP) staining, and pit formation assay were employed to investigate the role of TRPV5 in estrogen decreasing osteoclast differentiation and bone resorption. We found that the expression of TRPV5 is significantly down-regulated during estrogen deficiency-induced osteoclastogenesis. Furthermore, TRAP staining and pit formation assay showed that the depletion of TRPV5 significantly blocks the inhibitor effects of estrogen on osteoclasts differentiation and bone resorption activity. Further studies confirmed that estrogen regulates the expression of TRPV5 channel via estrogen receptor. Based on these results above, we can draw conclusion that TRPV5 may contribute to the process of estrogen-inhibited osteoclastogenesis and bone resorption activity.