A critical role of the Toll-like receptor(TLR) and its downstream molecules, including IL-1 receptor-associated kinase 1(IRAK1) and tumor necrosis factor receptor– associated factor 6(TRAF6), in the pathogenesis of liver ischemia/reperfusion (I/R) injury has been documented. Recently a microRNA, miR-146a, was identified as a potent negative regulator of the TLR signaling pathway. In this study, we investigated the role of miR-146a to attenuate TLR signaling and liver I/R injury in vivo and in vitro. miR-146a was decreased in mice Kupffer cells following hepatic I/R, whereas IRAK1 and TRAF6 increased. Overexpression of miR-146a directly decreased IRAK1 and TRAF6 expression and attenuated the release of proinflammatory cytokines through the inactivation of NF-κB P65 in hypoxia/reoxygenation (H/R)-induced macrophages, RAW264.7 cells. Knockdown experiments demonstrated that IRAK1 and TRAF6 are two potential targets for reducing the release of proinflammatory cytokines. Moreover, co-culture assays indicated that miR-146a decreases the apoptosis of hepatocytes after H/R. In vivo administration of Ago-miR-146a, a stable version of miR-146a in vivo, protected against liver injury in mice after I/R via inactivation of the TLR signaling pathway. We conclude that miR-146a ameliorates liver ischemia/reperfusion injury in vivo and hypoxia/reoxygenation injury in vitro by directly suppressing IRAK1 and TRAF6.

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Gastric cancer (GC) is an aggressive and highly lethal gastrointestinal cancer, with an exceedingly poor prognosis. In the present study, the carcinogenic mechanism of human GC and the role of cell division cycle-associated 3 (CDCA3) were investigated. The expression levels of CDCA3 were investigated in GC samples and matched, peritumoral tissues by reverse transcription-quantitative polymerase chain reaction and immunohistochemical analysis. The effects of CDCA3 on cell proliferation were explored by Cell Counting Kit-8, colony formation, flow cytometric analysis and western blotting in vitro, and in vivo tumorigenesis in nude mice. The results demonstrated that CDCA3 expression was increased in human GC tissues compared with those in adjacent non-tumor tissues. Evaluation of the clinicopathological significance indicated that CDCA3 was closely associated with features of GC and patients with unfavorable overall survival times. CDCA3 overexpression resulted in the stimulation of cell growth and colony formation in vitro and xenograft tumors in vivo. Conversely, knockdown of CDCA3 inhibited these effects. Furthermore, the ectopic expression of CDCA3 in SGC7901 cells consistently promoted the cell cycle transition from the G 0 /G 1 phase to the S phase; whereas knockdown of CDCA3 in BGC823 cells blocked the transition from the G 0 /G 1 phase. Additionally, the present study revealed that the Ras signaling pathway was involved in CDCA3-mediated regulation of GC cell proliferation. CDCA3 activated the Ras signaling pathway to promote cell proliferation in vitro and in vivo in GC cells. Levels of CDCA3 greatly accelerated the progression of human GC. CDCA3 served as an oncogene, and may be a significant prognostic predictor and a novel therapeutic target for patients with GC.

Nectins are Ca-independent immunoglobulin-like cell adhesion molecules that belong to a family of four members that function in a number of biological cellular activities. Nectin-4 is overexpressed in several types of human cancer; however, the functional and prognostic significance of Nectin-4 in gastric cancer (GC) remains unclear. In the present study, the reverse transcription-quantitative polymerase chain reaction and tissue microarray immunohistochemical analysis were used to investigate the expression of Nectin-4 in GC as well as its function in the prognosis of patients with GC. The results indicated that mRNA and protein expression of Nectin-4 were increased in tumor tissues compared with the matched non-tumor tissues. Expression of Nectin-4 was closely associated with differentiation (P=0.004), primary tumor (P=0.001), lymph node metastasis (P<0.001) and tumor-node-metastasis (TNM) stage (P<0.001). Positive Nectin-4 expression (P=0.001) and advanced TNM stage (P<0.001) were demonstrated to be associated with overall survival time in multivariate analyses. These results suggest that Nectin-4 may serve a significant function in GC and may serve as a novel clinic pathological biomarker and therapeutic target in GC.