Downregulation of microRNA-214 improves therapeutic potential of allogeneic bone marrow–derived mesenchymal stem cell by targeting PIM-1 in rats with acute liver failure

Acute liver failure (ALF) is a disease resulted from diverse etiology, which generally leads to a rapid degenerated hepatic function. However, transplantation bone marrow–derived mesenchymal stem cells (BMSCs) transplantation has been suggested to relieve ALF. Interestingly, microRNA-214 (miR-214) could potentially regulate differentiation and migration of BMSCs. The present study aims to inquire whether miR-214 affects therapeutic potential of BMSCs transplantation by targeting PIM-1 in ALF. 120 male Wistar rats were induced as ALF model rats and transplanted with BMSCs post-alteration of miR-214 or PIM-1 expression. Further experiments were performed to detect biochemical index (alanine aminotransferase [ALT], aspartate transaminase [AST], total bilirubin [TBiL]), and expression of miR-214, PIM-1, hepatocyte growth factor (HGF), caspase 3, tumor necrosis factor-α (TNF-α), and interleukin-10 (IL-10) in rat serum. Apart from the above detection, apoptosis of hepatocytes and Ki67 protein expression in hepatic tissues of rats were additionally assessed. After BMSCs transplantation with miR-214 inhibition, a decreased expression of ALT, AST, and TBiL yet an increased expression of HGF was shown, coupled with a decline in the expression of caspase 3, TNF-α, and IL-10. Meanwhile, alleviated hepatic injury and decreased apoptotic index of hepatic cells were observed and the positive rate of Ki67 protein expression was significantly increased. Moreover, miR-214 and caspase 3, TNF-α, and IL-10 decreased notably, while PIM-1 was upregulated in response to miR-214 inhibition. Strikingly, the inhibition of PIM-1 reversed effects triggered by miR-214 inhibition. These findings indicated that downregulation of miR-214 improves therapeutic potential of BMSCs transplantation by upregulating PIM-1 for ALF.     

Wnt7a,frequently silenced by CpG methylation,inhibits tumor growth and metastasis via suppressing epithelial-mesenchymal transition in gastric cancer

Wnt7a is a member of the Wnt family and has been reported to be involved in the carcinogenesis and progression of many types of human cancer. However, little is known about Wnt7a expression and function in gastric cancer (GC). In the present study, Wnt7a expression in GC tissues and cells was investigated, the correlation between Wnt7a expression and the prognosis was also examined. The effects of Wnt7a on proliferation, invasion, and metastasis were evaluated in vitro and in vivo. Furthermore, the expression of epithelial-mesenchymal transition (EMT) markers and hypermethylation of the Wnt7a promoter were both detected. Wnt7a was downregulated in GC and its expression was associated with poor prognosis of patients with GC. Moreover, upregulation of Wnt7a significantly suppressed the growth, invasion, and metastasis abilities of GC cells in vitro and in vivo. Mechanistically, Wnt7a was found to inhibit EMT process of GC cells. In addition, the reducing expression of Wnt7a was due to methylation of 5′-CpG island within the promoter. Furthermore, the tumor suppressor role of Wnt7a is independent of canonical Wnt/β-catenin signaling in GC cells. In conclusion, our findings demonstrated that Wnt7a could be used as a potential diagnostic marker and target for GC management.     

The discovery of a novel eight-mRNA-lncRNA signature predicting survival of hepatocellular carcinoma patients

Increasing evidence indicates that the expressions of messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs) undergo a frequent and aberrant change in carcinogenesis and cancer development. But some research was carried out on mRNA-lncRNA signatures for prediction of hepatocellular carcinoma (HCC) prognosis. We aimed to establish an mRNA-lncRNA signature to improve the ability to predict HCC patients’ survival. The subjects from the cancer genome atlas (TCGA) data set were randomly divided into two parts: training data set (n = 246) and testing data set (n = 124). Using computational methods, we selected eight gene signatures (five mRNAs and three lncRNAs) to generate the risk score model, which were significantly correlated with overall survival of patients with HCC in both training and testing data set. The signature had the ability to classify the patients in training data set into a high-risk group and low-risk group with significantly different overall survival (hazard ratio = 4.157, 95% confidence interval = 2.648-6.526, P < 0.001). The prognostic value was further validated in testing data set and the entire data set. Further analysis revealed that this signature was independent of tumor stage. In addition, Gene Set Enrichment Analysis suggested that high risk score group was associated with cell proliferation and division related pathways. Finally, we developed a well-performed nomogram integrating the prognostic signature and other clinical information to predict 3- and 5-year overall survival. In conclusion, the prognostic mRNAs and lncRNAs identified in our study indicate their potential role in HCC biogenesis. The risk score model based on the mRNA-lncRNA may be an efficient classification tool to evaluate the prognosis of patients’ with HCC.     

Microvesicles-mediated communication between endothelial cells modulates,endothelial survival,and angiogenic function via transferring of miR-125a-5p

Endothelial cells (ECs) released microvesicles (EMVs) could modulate the functions of target cells by transferring their microRNAs (miRs). We have reported that miR-125a-5p protected EC function. In this study, we determined whether EMVs provided beneficial effects on ECs by transferring miR-125a-5p. Human brain microvessel ECs were transfected with miR-125a-5p mimic or miR-125a-5p short hairpin RNA to obtain miR-125a-5p overexpressing ECs and miR-125a-5p knockdown ECs, and their derived EMVs. For the functional study, ECs or hypoxia/reoxygenation injured ECs were coincubated with various EMVs. The survival and angiogenic function of ECs were measured. Western blot and quantitative real time polymerase chain reaction (qRT-PCR) were used for measuring the levels of phosphoinositide 3-kinase (PI3K), phosphorylation-Akt (p-Akt)/Akt, p-endothelial nitric oxide synthase (p-eNOS), cleaved caspase-3, and miR-125a-5p. PI3K inhibitor was used for pathway analysis. EMVs promoted the proliferation, migration, and tube formation ability of ECs, and alleviated the apoptotic rate of ECs. These effects were associated by an increase in p-Akt/Akt and p-eNOS, and a decrease in cleaved caspase-3 could be abolished by LY294002. Overexpression or downregulation of miR-125a-5p in EMVs promoted or inhibited those effects of EMVs. EMVs could enhance the survival and angiogenic function of ECs via delivering miR-125a-5p to modulate the expression of PI3K/Akt/eNOS pathway and caspase-3.