TAZ is indispensable for c-MYC-induced hepatocarcinogenesis.

BACKGROUND & AIMS: Mounting evidence implicates the Hippo downstream effectors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) in hepatocellular carcinoma (HCC). We investigated the functional contribution of YAP and/or TAZ to c-MYC-induced liver tumor development. METHODS: The requirement for YAP and/or TAZ in c-Myc-driven hepatocarcinogenesis was analyzed using conditional Yap, Taz, and Yap;Taz knockout (KO) mice. An hepatocyte-specific inducible TTR-CreERT2 KO system was applied to evaluate the role of YAP and TAZ during tumor progression. Expression patterns of YAP, TAZ, c-MYC, and BCL2L12 were analyzed in human HCC samples. RESULTS: We found that the Hippo cascade is inactivated in c-Myc-induced mouse HCC. Intriguingly, TAZ mRNA levels and activation status correlated with c-MYC activity in human and mouse HCC, but YAP mRNA levels did not. We demonstrated that TAZ is a direct transcriptional target of c-MYC. In c-Myc induced murine HCCs, ablation of Taz, but not Yap, completely prevented tumor development. Mechanistically, TAZ was required to avoid c-Myc-induced hepatocyte apoptosis during tumor initiation. The anti-apoptotic BCL2L12 gene was identified as a novel target regulated specifically by YAP/TAZ, whose silencing strongly suppressed c-Myc-driven murine hepatocarcinogenesis. In c-Myc murine HCC lesions, conditional knockout of Taz, but not Yap, led to tumor regression, supporting the requirement of TAZ for c-Myc-driven HCC progression. CONCLUSIONS: TAZ is a pivotal player at the crossroad between the c-MYC and Hippo pathways in HCC. Targeting TAZ might be beneficial for the treatment of patients with HCC and c-MYC activation. LAY SUMMARY: The identification of novel treatment targets and approaches for patients with hepatocellular carcinoma is crucial to improve survival outcomes. We identified TAZ as a transcriptional target of c-MYC which plays a critical role in c-MYC-dependent hepatocarcinogenesis. TAZ could potentially be targeted for the treatment of patients with c-MYC-driven hepatocellular carcinoma.

Nesfatin-130-59 Injected Intracerebroventricularly Increases Anxiety, Depression-Like Behavior, and Anhedonia in Normal Weight Rats.

Nesfatin-1 is a well-established anorexigenic peptide. Recent studies indicated an association between nesfatin-1 and anxiety/depression-like behavior. However, it is unclear whether this effect is retained in obesity. The aim was to investigate the effect of nesfatin-130-59-the active core of nesfatin-1-on anxiety and depression-like behavior in normal weight (NW) and diet-induced (DIO) obese rats. Male rats were intracerebroventricularly (ICV) cannulated and received nesfatin-130-59 (0.1, 0.3, or 0.9 nmol/rat) or vehicle 30 min before testing. Nesfatin-130-59 at a dose of 0.3 nmol reduced sucrose consumption in the sucrose preference test in NW rats compared to vehicle (⁻33%, p < 0.05), indicating depression-like/anhedonic behavior. This dose was used for all following experiments. Nesfatin-130-59 also reduced cookie intake during the novelty-induced hypophagia test (-62%, p < 0.05). Moreover, nesfatin-130-59 reduced the number of entries into the center zone in the open field test (-45%, p < 0.01) and the visits of open arms in the elevated zero maze test (-39%, p < 0.01) in NW rats indicating anxiety. Interestingly, DIO rats showed no behavioral alterations after the injection of nesfatin-130-59 (p > 0.05). These results indicate an implication of nesfatin-130-59 in the mediation of anxiety and depression-like behavior/anhedonia under normal weight conditions, while in DIO rats, a desensitization might occur.

Fragile X-associated disorders: Don't miss them.

BACKGROUND: Fragile X-associated disorders are a family of inherited disorders caused by expansions in the Fragile X Mental Retardation 1 (FMR1) gene. Premutation expansions of the FMR1 gene confer risk for fragile X-associated primary ovarian insufficiency and fragile X-associated tremor ataxia syndrome, as well as other medical and psychiatric comorbidities. Premutation expansions of the FMR1 gene are common in the general population. However, fragile X-associated disorders are frequently under-recognised and often misdiagnosed. OBJECTIVE: The aim of this article is to describe fragile X-associated disorders and identify specific considerations for general practitioners (GPs) during identification and management of these disorders. DISCUSSION: GPs have a critical role in the identification of fragile X-associated disorders, as well as coordination of complex care needs. Prompt recognition and appropriate management of these disorders and potential medical and psychiatric comorbidities will have important implications not only for the affected patient, but also other family members who may be at risk.

[Association between grainyhead-like 2 gene polymorphisms and noise-induced hearing loss].

OBJECTIVE: To investigate association between genetic polymorphism in the grainyhead-like 2 gene (GRHL2) and noise-induced hearing loss (NIHL) in the Chinese population. METHODS: A matched case-control association study was employed, In which, 3 790 workers exposed to continuous and steady-state occupational noise in a steel factory participated. The questionnaires were adopted to collect individual features and audiometry tests performed. In the sstudy, 286 subjects were diagnosed as cases, Which were each designated on the basis of the matched criterion, and 286 paired samples were selected finally. Noise intensity was measured according to the standards given in 'Measurement of Noise in the Workplace'(Occupational Health Standard of the People's Republic of China, GBZ/T189.8-2007). Cumulative noise exposure (CNE) was calculated, according to monitoring data on A-weighed sound pressure level and employment time. Genomic DNA was obtained from peripheral blood samples using 2 mL DNA extraction Kit following the manufacturer's protocol. Five single nucleotide polymorphisms (SNPs) of GRHL2 were genotyped by multiplex SNP genotyping kit. The continuous variables and categorical variables were analyzed by t-test and chi-square test respectively. Multivariate Logistic regression was used to test the association between genetic frequency and disease status, with adjustments for the possible confounding variables. The haplotypes were established and their frequencies in the two groups were assessed by haploview and phase softwares. RESULTS: All the five SNPs (rs3735713, rs3824090, rs3735714, rs3735715 and rs611419) were in Hardy-Weinberg equilibrium (HWE) (P>0.05). The subjects carrying rs3735715 GG genotype had a higher NIHL risk than those carrying the GA genotype under the co-dominant model (OR=0.644, 95% CI: 0.442-0.939, P=0.022) after adjustment for height, blood pressure, drinking status and smoking status. After being stratified by CNE, in the CNE ≥ 98 dB (A) group, rs3735715 polymorphism was associated with the NIHL under the co-dominant model (OR=0.509, 95% CI: 0.281-0.923, P=0.026) after adjustment for height, blood pressure, drinking status and smoking status as well. However, no statistical significant difference was found in variant genotypes of the other SNPs between the case and control subjects. Four-locus (rs3735713, rs3824090, rs3735714 and rs3735715) haplotypes were constructed, and no risk or protective haplotypes was identified. CONCLUSION: It is suggested that GRHL2 polymorphisms may be associated with development of NIHL.

Effects of daintain/AIF-1 on ß cell dysfunction in INS-1 cells.

We investigated the effects of daintain/AIF-1, a novel inflammatory cytokine, on INS-1ß cells. Cells incubated with daintain/AIF-1 showed decreased cell viability and glucose-stimulated insulin secretion, as well as upregulated apoptosis and NO production. These deleterious effects of daintain/AIF-1 indicate that daintain/AIF-1 plays important roles in the dysfunction of pancreatic ß cells in type-1 diabetes.