Ubiquitin-specific protease 4 promotes hepatocellular carcinoma progression via cyclophilin A stabilization and deubiquitination.

Ubiquitin-specific protease 4 (USP4) is a member of the deubiquitinating enzyme family, which plays an important role in human tumor diseases. However, the mechanisms by which USP4 facilitates tumor development, especially in hepatocellular carcinoma (HCC), remain unclear. Clinically, we found that USP4 is overexpressed in human HCC tissues compared with adjacent non-tumoral tissues and is significantly correlated with malignant phenotype characteristics, including tumor size, tumor number, differentiation, serum alpha-fetoprotein level, and vascular invasion. Moreover, Kaplan-Meier survival analysis showed a poor overall survival rate in patients with USP4-overexpressing tumors. Analyses of univariate and multivariate Cox proportional hazard models indicated that USP4 is a prognostic biomarker for poor outcome. Using in vitro and in vivo assays, we demonstrated that USP4 overexpression enhanced HCC cell growth, migration, and invasion. Mechanistically, cyclophilin A (CypA) was identified as an important molecule for USP4-mediated oncogenic activity in HCC. We observed that USP4 interacted with CypA and inhibited CypA degradation via deubiquitination in HCC cells. Subsequently, the USP4/CypA complex activated the MAPK signaling pathway and prevented CrkII phosphorylation. These data suggest that USP4 acts as a novel prognostic marker, offering potential therapeutic opportunities for HCC.

MiRNA-211 suppresses cell proliferation, migration and invasion by targeting SPARC in human hepatocellular carcinoma.

Previous studies have shown that the expression of miR-211 was downregulated in hepatocellular carcinoma (HCC). However, the molecular function and mechanism of miR-211 in HCC growth and invasion are largely unclear. We found that miR-211 is downregulated in HCC tissues and cell lines, respectively. Further results showed that low miR-211 associated with TNM stage, vein invasion status, and poor prognosis. Ectopic expression of miR-211 effectively suppressed HCC cell proliferation, migration and invasion both in vitro and in vivo. We identified SPARC as a bona fide target of miR-211, and overexpression of miR-211 decreased the mRNA and protein expression of SPARC. Finally, we confirmed that the overexpression of SPARC in miR-211-expressing HCC cells can partially restore the inhibitory effect of miR-211. Taken together, our results demonstrated that loss of miR-211 expression and thus uncontrolled SPARC overexpression might drive progression of HCC, which may provide a novel therapeutic strategy for the treatment of HCC.

The reduction rate of serum C3 following liver transplantation is an effective predictor of non-anastomotic strictures.

PURPOSE: Non-anastomotic biliary strictures (NAS) are considered to be the thorniest complications following liver transplantation (LT). How to predict and adopt specific measures early to minimize the occurrence of it remains unclear. In this study, we aimed to find the relationship between the change rate of serum complement level and NAS. METHODS: In a series of 232 adult patients who underwent their first LT, serum C3 and C4 concentrations at predetermined time points were collected. The correlation between the change rate of serum complement level following LT and the clinical outcome of NAS was retrospectively studied. RESULTS: The reduction rate of serum C3 at the 1st day following LT in NAS patients was significantly different from that in non-NAS patients (p < 0.01). Receiver operating characteristic curve analysis demonstrated that the reduction rate of serum C3 is an effective predictor of NAS with an area under curve of 82.5 % (95 % CI 77.0-87.2 %). The reduction rate of C3 in the severe NAS group was significantly higher than that in the mild NAS group and the non-NAS group (p < 0.01). CONCLUSIONS: Complement activation plays important roles on the progression of NAS. The reduction rate of serum C3 is an effective predictor of NAS.