BackgroundKaposi's sarcoma-associated herpesvirus (KSHV) is causally linked to several acquired immunodeficiency syndrome-related malignancies, including Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and a subset of multicentric Castleman's disease. Regulation of viral lytic replication is critical to the initiation and progression of KS. Recently, we reported that herpes simplex virus type 1 (HSV-1) was an important cofactor that activated lytic cycle replication of KSHV. Here, we further investigated the possible signal pathways involved in HSV-1-induced reactivation of KSHV.ResultsBy transfecting a series of dominant negative mutants and protein expressing constructs and using pharmacologic inhibitors, we found that either Janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3) or JAK1/STAT6 signaling failed to regulate HSV-1-induced KSHV replication. However, HSV-1 infection of BCBL-1 cells activated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB, also called AKT) pathway and inactivated phosphatase and tensin homologue deleted on chromosome ten (PTEN) and glycogen synthase kinase-3β (GSK-3β). PTEN/PI3K/AKT/GSK-3β pathway was found to be involved in HSV-1-induced KSHV reactivation. Additionally, extracellular signal-regulated protein kinase (ERK) mitogen-activated protein kinase (MAPK) pathway also partially contributed to HSV-1-induced KSHV replication.ConclusionsHSV-1 infection stimulated PI3K/AKT and ERK MAPK signaling pathways that in turn contributed to KSHV reactivation, which provided further insights into the molecular mechanism controlling KSHV lytic replication, particularly in the context of HSV-1 and KSHV co-infection.

While the application of early screening and HPV vaccines has reduced the incidence and mortality rates of cervical cancer, it remains the third most common carcinoma and fourth leading cause of cancer-associated death among women worldwide. The precise mechanisms underlying progression of cervical cancer are not fully understood at present. Here, we detected significant down-regulation of 15-hydroxyprostaglandin dehydrogenase (HPGD) in cervical cancer tissues. Overexpression of HPGD inhibited cervical cancer cell proliferation, migration and anchorage-independent growth to a significant extent. To clarify the mechanisms underlying HPGD down-regulation in cervical cancer, miRNA microarray, bioinformatics and luciferase reporter analyses were performed. HPGD was identified as a direct target of miR-146b-3p displaying up-regulation in cervical cancer tissues. Similar to the effects of HPGD overexpression, down-regulation of miR-146b-3p strongly suppressed proliferation, migration and anchorage-independent growth of cervical cancer cells. Furthermore, HPGD negatively regulated activities of STAT3 and AKT that promote cervical cancer cell proliferation. Notably, HPV oncogenes E6 and E7 were determined as potential contributory factors to these alterations. Our results collectively suggest that the HPGD/miR-146b-3p axis plays a significant role in cervical cancer and may serve as a potentially effective therapeutic target.

Individual studies of the associations between excision repair cross-complimentary group 1 (ERCC1) polymorphisms and cancer susceptibility have shown inconclusive results. To derive a more precise estimation of the relationship between three well-characterised polymorphisms on ERCC1 and the risk of cancer, we performed a meta-analysis based on 48 publications. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the associations. We found that ERCC1 17677A (rs3212961) variant genotypes were associated with significantly increased overall risk of cancer without substantial heterogeneity (AA versus CC, OR = 1.36, 95% CIs: 1.10-1.68; AC versus CC: OR = 1.11, 95% CIs: 0.99-1.26; dominant comparison: AA/AC versus CC: OR = 1.15, 95% CIs: 1.02-1.29; recessive comparison: AA versus AC/CC: OR = 1.25, 95% CIs: 1.05-1.49). The ERCC1 19007 C (rs11615) allele had null effects on overall risk of cancer; but in the stratified analyses, we observed an elevated association in Asian populations with homozygote variants and hospital-based controls. In addition, during further stratified analyses of cancer groups, homozygote variants were found that are associated with lung cancer and smoking-related cancers. Also, the observed ERCC1 19007 C heterozygote variant contributes to the development of skin cancer. However, the ERCC1 8092C > A (rs3212986) polymorphism did not appear to have an effect on cancer risk. Additionally, no evidence of publication bias was observed in these polymorphisms. Our meta-analysis supports the conclusion that the ERCC1 17677A > C and ERCC1 19007T > C polymorphisms, but not the ERCC1 8092C > A polymorphism, are low-penetrance risk factors for cancer development.

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BackgroundCancer/testis antigens (CTAs) are a special type of tumor antigen and are believed to act as potential targets for cancer immunotherapy.MethodsIn this study, we first screened a rational CTA MAGE-A1 for lung adenocarcinoma (LUAD) and explored the detailed characteristics of MAGE-A1 in LUAD development through a series of phenotypic experiments. Then, we developed a novel MAGE-A1-CAR-T cell (mCART) using lentiviral vector based on our previous MAGE-A1-scFv. The anti-tumor effects of this mCART were finally investigated in vitro and in vivo.ResultsThe results showed striking malignant behaviors of MAGE-A1 in LUAD development, which further validated the rationality of MAGE-A1 as an appropriate target for LUAD treatment. Then, the innovative mCART was successfully constructed, and mCART displayed encouraging tumor-inhibitory efficacy in LUAD cells and xenografts.ConclusionsTaken together, our data suggest that MAGE-A1 is a promising candidate marker for LUAD therapy and the MAGE-A1-specific CAR-T cell immunotherapy may be an effective strategy for the treatment of MAGE-A1-positive LUAD.