The miR-34 family members are direct transcriptional targets of tumor suppressor p53, and loss of miR-34 function can impair p53-mediated cell cycle arrest and apoptosis. A potentially functional SNP rs4938723 (T > C) was found in the promoter region of pri-miR-34b/c (423 bp from the transcription start site), located in the CpG island and might affect transcription factor GATA binding and therefore pri-miR-34b/c expression. In our study, we hypothesized that SNPs miR-34b/c rs4938723 and TP53 Arg72Pro may independently or jointly contribute to primary hepatocellular carcinoma (HCC) susceptibility. We then genotyped the 2 SNPs in a case-control study of 501 patients with primary HCC and 548 cancer-free controls in a Chinese population. We observed that the variant genotypes of miR-34b/c rs4938723 were associated with significantly increased HCC risks compared with the wild-type TT genotype (adjusted OR 5 1.37, 95% CI 51.06-1.78 for TC; OR 5 1.53, 95% CI 5 1.02-2.31 for CC and OR 5 1.40, 95% CI 5 1.10-1.80 for TC/CC). Furthermore, we found a significant interaction between alcohol drinking and SNP rs4938723 on HCC risk (p 5 0.05 for multiplicative and p 5 0.01 for additive interaction). However, we did not find any main effect of TP53 Arg72Pro on HCC risk in this population. These findings indicate that the potentially functional SNP rs4938723 in the promoter region of pri-miR-34b/c may contribute to the susceptibility of HCC in this Chinese population.Hepatocellular carcinoma (HCC) is the sixth most common malignancy and the third leading cause of cancer-related death worldwide. The distribution of HCC is imbalance throughout the world, and 82% of the cases (and the deaths) are estimated in developing countries (55% in China alone). 1The major risk factors for HCC are chronic infections with the hepatitis B or C viruses, exposure to dietary aflatoxin B1 and alcohol consumption, 2 with the hepatitis B virus (HBV) infection of particular interest, because of its coherent distribution with the HCC prevalence.

CD8+ T cells are critical in the balance between fetal tolerance and antiviral immunity. T-cell immunoglobulin mucin-3 (Tim-3) and programmed cell death-1 (PD-1) are important negative immune regulatory molecules involved in viral persistence and tumor metastasis. Here, we demonstrate that Tim-3+PD-1+CD8+ T cells from decidua greatly outnumbered those from peripheral blood during human early pregnancy. Co-culture of trophoblasts with CD8+ T cells upregulated PD-1+ and/or Tim-3+ immune cells. Furthermore, the population of CD8+ T cells co-expressing PD-1 and Tim-3 was enriched within the intermediate memory subset in decidua. This population exhibited high proliferative activity and Th2-type cytokine producing capacity. Blockade of Tim-3 and PD-1 resulted in decreased in vitro proliferation and Th2-type cytokine production while increased trophoblast killing and IFN-γ producing capacities of CD8+ T cells. Pregnant CBA/J females challenged with Tim-3 and/or PD-1 blocking antibodies were more susceptible to fetal loss, which was associated with CD8+ T-cell dysfunction. Importantly, the number and function of Tim-3+PD-1+CD8+ T cells in decidua were significantly impaired in miscarriage. These findings underline the important roles of Tim-3 and PD-1 pathways in regulating decidual CD8+ T-cell function and maintaining normal pregnancy.

It has been shown that long noncoding RNAs (lncRNAs) play a critical role in the regulation of cellular processes including cancer progression and metastasis. However, the biological functions and clinical significance of lncRNA AFAP1-AS1 in hepatocellular carcinoma (HCC) remain unclear. Expression of AFAP1-AS1 was analyzed in 78 HCC tissues by real-time PCR. The effect of AFAP1-AS1 on cell proliferation was examined by MTT assay, cell apoptosis was detected by flow cytometric analysis and cell invasion was determined by Transwell assay. RhoA/Rac2 signaling and downstream factors were verified by western blotting. HCC cells infected with si-AFAP1-AS1 were injected into nude mice to investigate the effect of AFAP1-AS1 on the tumorigenesis in vivo. We found that increased expression of AFAP1-AS1 was significantly correlated with pathological staging (P=0.024) and lymph-vascular space invasion (LVSI) in HCC patients (P=0.007). Multivariate analyses indicated that AFAP1-AS1 represented an independent predictor for overall survival of HCC (P=0.029). Further experiments showed that knockdown of AFAP1-AS1 by si-AFAP1-AS1 decreased the proliferation and invasion in vitro and in vivo, induced cell apoptosis and blocked cell cycle in S phase via inhibition of the RhoA/Rac2 signaling. Taken together, our findings indicate that AFAP1-AS1 may promote the HCC development through upregulation of RhoA/Rac2 signaling and provide a potential therapeutic target for HCC.

Aim: To test the role of the Beclin 1-dependent autophagy pathway in brain damage during cerebral ischemia. Methods: Focal cerebral ischemia was established in rats using a middle cerebral artery occlusion (MCAO) model. A lentiviral vectorassociated RNA interference (RNAi) system was stereotaxically injected into the ipsilateral lateral ventricle to reduce Beclin1 expression. We measured the ipsilateral infarct volume, autophagosome formation, neurogenesis and apoptosis, all of which could be modulated by Beclin1 RNAi. Results: On the 14th day after MCAO, Beclin1 downregulation by RNAi increased the population of neural progenitor cells (BrdU + -DCX + ), newborn immature cells (BrdU + -Tuj-1 + ) and mature neurons (BrdU + -MAP-2 + ), and reduced the apoptosis of immature neurons (caspase-3 + -DCX + and caspase-3 + -Tuj-1 + ) surrounding the ischemic core of the ipsilateral hemisphere. Furthermore, RNAi-mediated downregulation of Beclin1 decreased infarct volume and inhibited histological injury and neurological deficits. Conclusion: RNAi-mediated downregulation of Beclin1 improves outcomes after transient MCAO.