APCCDC20-mediated degradation of PHD3 stabilizes HIF-1a and promotes tumorigenesis in hepatocellular carcinoma.

CDC20 regulates cell cycle progression by targeting key substrates for destruction, but its role in hepatocellular carcinoma (HCC) tumorigenesis remains to be explored. Here, by using weighted gene co-expression network analysis (WGCNA), we identified CDC20 as a hub gene in HCC. We demonstrated that CDC20 expression is correlated with HIF-1 activity and overall survival (OS) of clinic HCC patients. The activity of HIF-1 is regulated by the stability of HIF-1a subunit, which is hydroxylated by oxygen-dependent prolyl hydroxylase enzymes, the PHDs. In addition, we show that genetic ablation or pharmacological inhibition of CDC20 can accelerate the degradation of HIF-1a and impair VEGF secretion in HCC cells. Mechanistically, we found that CDC20 binds to the destruction-box (D-box) motif present in the PHD3 protein to promote its polyubiquitination and degradation. The depletion of endogenous PHD3 in CDC20 knockdown HCC cells greatly attenuated the decline of HIF-1a protein and restored the secretion of VEGF. In contrast, overexpression of a non-degradable PHD3 mutant significantly inhibited the proliferation of HCC cells both in vitro and in vivo. Collectively, our findings indicate that CDC20 plays a crucial role in the development of HCC by governing PHD3 protein.

Association between LKB1 expression and prognosis of patients with solid tumours: an updated systematic review and meta-analysis.

OBJECTIVES: Liver kinase B1 (LKB1) is considered a tumour suppressor that can control cell growth and metabolism. Whether LKB1 expression levels are related to clinicopathology and prognosis is controversial. This review aimed to quantitatively examine the latest evidence on this question. DESIGN: An updated systematic review and meta-analysis on the association between LKB1 expression and prognosis of patients with solid tumours were performed. DATA SOURCES: Eligible studies were identified through literature searches from database establishment until 15 June 2018 in the following databases: Embase, PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure and Wan Fang databases. ELIGIBILITY CRITERIA: The association between LKB1 expression and clinicopathological characteristics, overall survival (OS), disease-free survival (DFS) and relapse-free survival (RFS) of patients with solid tumours were reported. Sufficient data were available to calculate the OR or HR and 95% CI. DATA EXTRACTION AND SYNTHESIS: Relevant data were meta-analysed for OS, DFS, RFS and various clinical parameters. RESULTS: The systematic review included 25 studies containing 6012 patients with solid tumours. Compared with patients with high LKB1 expression, patients with low expression showed significantly shorter OS in univariate analysis (HR=1.63, 95% CI 1.35 to 1.97, p<0.01) and multivariate analysis (HR=1.61, 95% CI 1.26 to 2.06, p<0.01). In contrast, the two groups showed similar DFS in univariate analysis (HR=1.49, 95% CI 0.73 to 3.01, p=0.27) as well as similar RFS in univariate analysis (HR=1.44, 95% CI 0.65 to 3.17, p=0.37) and multivariate analysis (HR=1.02, 95% CI 0.42 to 2.47, p=0.97). Patients with low LKB1 expression showed significantly worse tumour differentiation (OR=1.71, 95% CI 1.14 to 2.55, p<0.01), larger tumours (OR=1.68, 95% CI 1.24 to 2.27, p<0.01), earlier lymph node metastasis (OR=1.43, 95% CI 1.26 to 1.62, p<0.01) and more advanced tumour, node, metastases (TNM) stage (OR=1.80, 95% CI 1.56 to 2.07, p<0.01). CONCLUSION: Low LKB1 expression predicts shorter OS, worse tumour differentiation, larger tumours, earlier lymph node metastasis and more advanced TNM stage. Low LKB1 expression may be a useful biomarker of poor clinicopathology and prognosis.

Serum Prealbumin is Negatively Associated with Survival in Hepatocellular Carcinoma Patients after Hepatic Resection.

Objective: Low serum prealbumin levels are associated with poor prognoses in some type of cancers. However, the role of prealbumin in patients with hepatocellular carcinoma (HCC) is unknown. The present study aimed to investigate the role of serum prealbumin levels in long-term survival for HCC patients after hepatic resection. Methods: HCC patients who underwent hepatic resection from June 2007 to December 2015 were retrospectively analyzed in a tertiary liver center. Patients were classified as having normal or reduced serum prealbumin based on a cut-off value of 200 mg/L. Overall survival and recurrence rate were analyzed between groups. Propensity score analysis was used to reduce bias due to other patient differences at baseline. Results: A total of 1349 HCC patients who underwent hepatic resection were enrolled on this study, including 1168 (86.6%) male and 181 (13.4%) female. Patients with normal serum prealbumin had significantly higher overall survival than those with reduced serum prealbumin (P < 0.001). Similar findings were observed after propensity analysis and subgroup analysis based on liver cirrhosis. Moreover, patients with normal serum prealbumin had a significantly lower recurrence rate than those with reduced serum prealbumin (P < 0.001). Conclusions: Low preoperative level of serum prealbumin is associated with poor long-term survival in patients with HCC after hepatic resection. Low serum prealbumin may be a marker to identify patients at high risk of poor prognosis after hepatic resection.

Correlation between serum prealbumin and prognosis of patients with hepatocellular carcinoma after hepatectomy.

OBJECTIVE: To determine whether serum prealbumin levels are associated with long-term survival after hepatectomy in patients with primary hepatocellular carcinoma(HCC). METHODS: A consecutive sample of 526 patients with HCC who underwent potentially curative hepatectomy from August 2007 to August 2010 was retrospectively analyzed. Patients were classified as having normal or reduced serum prealbumin based on cut-off values of 200 or 182 mg/L. RESULTS: Multivariate analysis identified the preoperative level of serum prealbumin as an independent prognostic factor of long-term survival (P < 0.05): Survival was significantly better for those with normal levels than for those with reduced levels, based on either cut-off value. Similar results were observed in subgroup analyses based on the degree of cirrhosis, level of ɑ-fetoprotein and Barcelona Clinic Liver Cancer stage. CONCLUSIONS: Preoperative level of serum prealbumin may be useful for predicting long-term survival in patients with HCC after hepatectomy.

Could ADC values be a promising diagnostic criterion for differentiating malignant and benign hepatic lesions in Asian populations: A meta-analysis.

BACKGROUND: Liver cancer exhibits geographic and ethnic differences in its prevalence and biology, which implies that it is impractical to develop universal guidelines for all patients. Thus, a meta-analysis was conducted to identify the accuracy of apparent diffusion coefficients (ADCs) for discriminating malignant from benign liver lesions in Asians. METHODS: Eligible studies published in PubMed, Ovid, and Embase/Medline were updated onto October 2014. STATA 12.0 and Meta-Disc 1.4 were used to perform this meta-analysis. RESULTS: Eight studies comprising 661 benign liver lesions and 598 malignant liver lesions fulfilled all the inclusion criteria. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 0.88 (95% confidence interval [CI] 0.75-0.95), 0.93 (95% CI 0.86-0.97), 12.42 (95% CI 6.09-25.31), 0.13 (95% CI 0.06-0.29), and 95.58 (95% CI 35.29-258.89), respectively. Overall, the area under the summary receiver-operating characteristic curve was 0.96 (95% CI 0.94-0.98). Heterogeneity was found to originate potentially from the type of benign lesion. A subgroup analysis showed that differentiating between hemangiomas, cysts, and malignant liver lesions produced a significantly higher diagnostic accuracy than that of solid liver lesions. CONCLUSION: Our meta-analysis indicated that ADC could be promising for characterizing liver lesions among Asians, indicating that the ADC value is a promising diagnostic criterion candidate. Meanwhile, the use of dual b values could be sufficient for liver lesion characterization. However, large-scale, high-quality trials should be conducted to identify specific standards, including cut-off values for further development of diffusion-weighted imaging as a routine clinical application among Asian populations.

DDR2 Induces Gastric Cancer Cell Activities via Activating mTORC2 Signaling and Is Associated with Clinicopathological Characteristics of Gastric Cancer.

BACKGROUND/AIM: Epithelial-mesenchymal transition (EMT) plays a role in cancer progression. Previous studies have suggested that discoidin domain receptor 2 (DDR2) is related to tumor progression and EMT. However, the role of DDR2 in regulating gastric cancer (GC) metastasis and in EMT has not been elucidated. In this study, we aimed to determine DDR2 expression and its clinical relation in GC and to investigate the effects of DDR2 on EMT and its underlying mechanisms. METHODS: DDR2 expression and the relation to patients' clinicopathological features were assayed by Western blot or immunohistochemical staining. The effects of DDR2 overexpression were investigated using in vivo tumorigenicity and xenograft models. The effects of DDR2 on EMT marker expression were assayed by Western blot and immunofluorescence. The possible role of the mTORC pathway in these processes was explored. RESULTS: DDR2 showed high expression in GC tissues and cells. DDR2 expression was negatively correlated with E-cadherin expression and positively correlated with N-cadherin and vimentin expression. High DDR2 expression is correlated with unfavorable pathoclinical features such as multiple tumor locations and intestinal-type GC. In xenograft models, DDR2 overexpression promoted tumor formation. Furthermore, DDR2 expression impacted on the invasion and motility of GC cells, accompanied by changes in EMT marker expression. Finally, our results revealed that DDR2 facilitates GC cell invasion and EMT through mTORC2 activation and AKT phosphorylation. CONCLUSION: DDR2 is upregulated and correlated with unfavorable clinical features of GC patients. DDR2 promotes tumor formation and invasion through facilitating EMT process via mTORC2 activation and AKT phosphorylation.

Comparison of Existing Clinical Scoring Systems in Predicting Severity and Prognoses of Hyperlipidemic Acute Pancreatitis in Chinese Patients: A Retrospective Study.

It is important to identify the severity of acute pancreatitis (AP) in the early course of the disease. Clinical scoring systems may be helpful to predict the prognosis of patients with early AP; however, few analysts have forecast the accuracy of scoring systems for the prognosis in hyperlipidemic acute pancreatitis (HLAP). The purpose of this study was to summarize the clinical characteristics of HLAP and compare the accuracy of conventional scoring systems in predicting the prognosis of HLAP. This study retrospectively analyzed all consecutively diagnosed AP patients between September 2008 and March 2014. We compared the clinical characteristics between HLAP and nonhyperlipidemic acute pancreatitis. The bedside index for severity of acute pancreatitis (BISAP), Ranson, computed tomography severity index (CTSI), and systemic inflammatory response syndrome (SIRS) scores were applied within 48 hours following admission. Of 909 AP patients, 129 (14.2%) had HLAP, 20 were classified as severe acute pancreatitis (SAP), 8 had pseudocysts, 9 had pancreatic necrosis, 30 had pleural effusions, 33 had SIRS, 14 had persistent organ failure, and there was 1 death. Among the HLAP patients, the area under curves for BISAP, Ranson, SIRS, and CTSI in predicting SAP were 0.905, 0.938, 0.812, and 0.834, 0.874, 0.726, 0.668, and 0.848 for local complications, and 0.904, 0.917, 0.758, and 0.849 for organ failure, respectively. HLAP patients were characterized by younger age at onset, higher recurrence rate, and being more prone to pancreatic necrosis, organ failure, and SAP. BISAP, Ranson, SIRS, and CTSI all have accuracy in predicting the prognosis of HLAP patients, but each has different strengths and weaknesses.