Inflammation is well known as an important driver of the initiation of colitis-associated cancer (CAC). Some cytokines, such as IL-6 and TNF- can activate expression of the oncogene c-Myc (MYC) and regulate its downstream effects. Cullin-RING E3 Ligases (CRLs) are emerging as master regulators controlling tumorigenesis.Here, we demonstrate that two cullin genes, CUL4A and CUL4B, but not other members, are specifically overexpressed in CAC tumour samples and positively correlate with levels of the proinflammatory cytokines IL-1 and IL-6. In vitro experiments revealed that the transcription factor c-Myc can specifically activate the expression of CUL4A and CUL4B by binding to a conserved site (CACGTG) located in their promoters. Additionally, we found that both CUL4A and CUL4B can form an E3 complex with DNA damage-binding protein 1 (DDB1) and DDB1-CUL4-associated factor 4 (DCAF4). In vitro and in vivo ubiquitination analyses indicate that CRL4 DCAF4 E3 ligase specifically directs degradation of ST7 (suppression of tumorigenicity 7). Overexpression of c-Myc in human colon epithelial cells resulted in the accumulation of CUL4A, CUL4B and DCAF4, but degradation of ST7. In contrast, knockdown of c-Myc, CUL4A or CUL4B in the colon adenocarcinoma cell line HT29 caused accumulation of ST7 and inhibition of cell proliferation, colony formation ability and in vivo tumour growth. Collectively, our results provide in vitro and in vivo evidence that c-Myc regulates CRL4 DCAF4 E3 ligase activity to mediate ubiquitination of ST7, whose presence is physiologically essential for CAC tumorigenesis.No conflicts of interest were declared. ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s) [16,17]. The human genome encodes two E1s, ∼40 E2s and more than 600 E3s [18,19]. Of these E3 ligases, Cullin-RING

Background:In recent years, an increasing number of studies has been published analyzing the possible prognostic utility of glypican-3 (GPC3) in hepatocellular carcinoma (HCC), but the results are still controversial. The aim of this meta-analysis was to evaluate possible association between GPC3 expression and patients’ survival.Methods:Relevant publications which assessed GPC3 expression with survival outcome in HCC patients were searched from Pubmed, Embase, Web of Science, and the Cochrane library. Survival outcome (odds ratios or hazard ratios) was synthesized with a fixed or random effects meta-analysis. Publication bias and sensitivity analyses were also conducted. Statistical analysis was performed by STATA 12.0 and Review Manager software 5.3.Results:Fifteen studies including 2336 HCC cases were analyzed systematically in our meta-analysis. The main results showed that GPC3 high expression was significantly associated with later tumor stage, higher tumor grade, presence of vascular invasion, shortened overall survival, and disease-free survival. Subgroup analyses for GPC3 on HCC overall survival according to the studies categorized by sample size, follow-up period, and cut-offs were also conducted.Conclusion:Our findings suggested that GPC3 may play a role in cancer invasion and progression and may be related to poor prognosis of HCC. Further mechanical research or multicenter cohort studies are needed to confirm these findings.

The transcription factor c-Myc and two cullin family members CUL4A/4B function as oncogenes in colorectal cancer. Our recent publication reveals that c-Myc specifically activates the expression of CUL4A/4B through binding to their promoters. However, the underlying mechanism of how c-Myc actions in this process is still unknown. Using mass spectrometry and immunoprecipitation assays, we identified c-Myc formed a transcriptional complex with its partner Max (Myc-associated factor X), a histone acetyltransferase p300 and a coactivator associated arginine methyltransferase 1 (CARM1) in the present study. Knockdown or overexpression of the components of CARM1-p300-c-Myc-Max (CPCM) complex resulted in a decrease or increase of CUL4A/4B levels, respectively. Individual knockdown or inhibition of CPCM components decreased cell proliferation, colony formation, and cell invasion. Biochemically, knockdown or inhibition of CPCM components decreased their occupancies on the promoters of CUL4A/4B and resulted in their downregulation. Importantly, inhibition of CPCM components also caused a decrease of CRL4 E3 ligase activities and eventually led to an accumulation of ST7 (suppression of tumorigenicity 7), the specific substrate of CRL4 E3 ligases in colorectal cancer. Moreover, the in vivo tumor formation results indicated that knockdown or inhibition of CPCM components significantly decreased the tumor volumes. Together, our results suggest that the CPCM complex mediates explicitly the expression of CUL4A/4B, and thus affects the stability of CRL4 E3 ligases and the ubiquitination of ST7. These results provide more options by targeting the CPCM components to inhibit tumor growth in the therapy of colorectal cancer.

Purpose Based on the person-environment (P-E) fit theory, this study aims to explore the effect of customer mistreatment on the reduced service performance of hospitality employees mediated by person-job (P-J) fit perceptions and moderated by job crafting. Design/methodology/approach The authors tested this study’s hypotheses with a nine-day diary study involving 83 service employees located in Lanzhou, China; a total of 548 daily surveys were completed. The authors used multilevel structural equation modeling to analyze the data. Findings Employees who experienced daily customer mistreatment suffered diminished P-J fit perceptions, leading to lower levels of service performance the next day. In addition, job crafting significantly buffered the impact of customer mistreatment on P-J fit perceptions and the indirect impact of customer mistreatment on service performance through P-J fit perceptions. Practical implications Given the damaging effect that customer mistreatment has on service performance, where employees’ P-J fit perceptions are impaired, hotel managers should implement service competence improvement training programs and managerial preventions to reduce the possibility of customer mistreatment behavior. The moderating role of job crafting behavior suggests that managers should offer supportive practices (i.e. job autonomy) to encourage job crafting behaviors among employees. Originality/value This study reveals that individuals’ P-J fit perceptions can explain the damaging impacts of customer mistreatment on service performance, a finding that contributes valuable information to the literature on customer mistreatment and P-E fit. Second, this study also tests the impact of individuals’ job crafting behaviors in terms of mitigating the negative effect of customer mistreatment. Finally, this study’s findings broaden the scope of predictors of P-J fit perceptions by revealing that customer mistreatment can pose a threat to hospitality employees’ P-J fit perceptions.

No abstract