Platinum chemotherapeutics are widely used to treat solid malignant tumors, including gastric cancer (GC). Drug resistance to platinum compounds may result in cancer relapse and decreased survival. The identification and development of novel agents to reactivate apoptosis pathways in platinum-resistant cancer cells is therefore necessary. Here we report that cisplatin-resistant human GC cells (BGC823/DDP and SGC7901/DDP) but not their parental cells (BGC823 and SGC7901) exhibit high sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as a result of overexpression of death receptor 4 (DR4). Furthermore, we found that JWA, a molecule that promotes cisplatin-induced apoptosis in GC cells, suppressed TRAIL-induced apoptosis via negative regulation of DR4. Mechanistically, JWA promoted the ubiquitination of DR4 at K273 via upregulation of the ubiquitin ligase membrane-associated RING-CH-8 (MARCH8). In human GC tissues, JWA and DR4 protein levels were negatively correlated. Thus TRAIL may serve as an auxiliary treatment for cisplatin-resistant GC, and JWA may be a potential predictive marker of TRAIL sensitivity and may improve personalized therapeutics for treating human GC.
Taken together, our results provided the potential evidence that rs10719 and rs493760 might contribute to the risk of CL/P and suggested potential genetic basis and mechanisms of CL/P. The lack of association between these SNPs and CPO might be due to the limited sample size of CPO subgroup.
Nonsyndromic orofacial clefts (NSOCs) are congenital newborn malformations. Myosin heavy chain 9 ( MYH9) is a candidate gene of NSOCs. To investigate the associations between single-nucleotide polymorphisms (SNPs) of MYH9 and NSOC susceptibility, a 2-stage case-control study was designed and 4 potentially functional SNPs of MYH9 (rs12107, rs2269529, rs9619601, rs5756130) were selected and genotyped by iPLEX Sequenom MassARRAY and TaqMan assay in the first stage (599 NSOC cases and 590 controls). The significant SNPs in the first stage were replicated in the second stage (676 NSOC cases and 705 controls) by TaqMan assay. Reverse transcription polymerase chain reaction, cell transfection, and luciferase assay were performed accordingly to explore their functionality. In stage I, rs12107 was nominally associated with NSOCs, whereas rs2269529 showed a significant association (rs12107: P = 0.028; rs2269529: P = 0.001). In stage II, rs12107 was nominally associated with NSOCs, and rs2269529 showed a significant association (rs12107: P = 0.014; rs2269529: P = 0.006). In combined stages, these 2 SNPs gained significant associations (rs12107: P = 0.004; rs2269529: P = 4.4 × 10). In subphenotype analysis, these 2 SNPs were associated with cleft lip only (CLO) and cleft lip with palate (CLP), and rs2269529 was also associated with cleft palate only (CPO). Haplotype analysis revealed associations between rs12107-G/rs2269529-T and NSOC susceptibility ( P = 0.011). Combined analysis of rs12107 and rs2269529 indicated the risk of NSOCs increased with the number of risk alleles (rs12107-G and rs2269529-T, P for trend = 0.008). MYH9 SNP rs12107 AG + GG and rs2269529 CT + TT were associated with higher MYH9 expression in lip tissues compared with their corresponding wild-type homozygote. For rs12107, higher luciferase activities of G allele than A allele were observed in the luciferase assay. MYH9 was downregulated when transfecting its putative binding target miR-196b-3p into human embryo plate mesenchyme (HEPM) and C2C12 cell lines. For rs2269529, C > T contributed to increased MYH9 messenger RNA. In conclusion, rs12107 and rs2269529 were associated with the expression of MYH9 and contributed to the susceptibility of NSOCs.
Social cooperation is fundamentally important for group animals but rarely studied with mice because of their natural aggressiveness. In the present work, we induced pairs of male mice to develop a mutualistic cooperative behavior in a non-divided chamber. Each mouse is first trained to learn to use a water dispenser by occupying a particular zone served as a switch to the dispenser. Two trained mice were then put into a chamber containing two separate zones jointly controlling two dispensers. We record the latency before each co-drinking, the number and cumulated time of co-drinking each day during the test. These parameters serve as quantitative measurements of cooperative behavior in mice. The whole procedure includes preparation, training, and testing phases, which take 16 days in total. This assay provides detailed procedures and analytical methods for investigators to characterize and quantify the mutualistic cooperative behavior. The use of mice as subjects allows convenient coupling to other behavior assays and is amiable to genetic manipulations for mechanistic study.
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