Lecithin-cholesterol acyltransferase is a potential tumor suppressor and predictive marker for hepatocellular carcinoma metastasis

BACKGROUND Hepatocellular carcinoma(HCC)is a major cause of cancer mortality worldwide,and metastasis is the main cause of early recurrence and poor prognosis.However,the mechanism of metastasis remains poorly understood.AIM To determine the possible mechanism affecting HCC metastasis and provide a possible theoretical basis for HCC treatment.METHODS The candidate molecule lecithin-cholesterol acyltransferase(LCAT)was screened by gene microarray and bioinformatics analysis.The expression levels of LCAT in clinical cohort samples was detected by quantitative realtime polymerase chain reaction and western blotting.The proliferation,migration,invasion and tumor-forming ability were measured by Cell Counting Kit-8,Transwell cell migration,invasion,and clonal formation assays,respectively.Tumor formation was detected in nude mice after LCAT gene knockdown or overexpression.The immunohistochemistry for Ki67,E-cadherin,N-cadherin,matrix metalloproteinase 9 and vascular endothelial growth factor were performed in liver tissues to assess the effect of LCAT on HCC.Gene set enrichment analysis(GSEA)on various gene signatures were analyzed with GSEA version 3.0.Three machine-learning algorithms(random forest,support vector machine,and logistic regression)were applied to predict HCC metastasis in The Cancer Genome Atlas and GEO databases.RESULTS LCAT was identified as a novel gene relating to HCC metastasis by using gene microarray in HCC tissues.LCAT was significantly downregulated in HCC tissues,which is correlated with recurrence,metastasis and poor outcome of HCC patients.Functional analysis indicated that LCAT inhibited HCC cell proliferation,migration and invasion both in vitro and in vivo.Clinicopathological data showed that LCAT was negatively associated with HCC size and metastasis(HCC size≤3 cm vs 3-9 cm,P<0.001;3-9 cm vs>9 cm,P<0.01;metastatic-free HCC vs extrahepatic metastatic HCC,P<0.05).LCAT suppressed the growth,migration and invasion of HCC cell lines via PI3K/AKT/mTOR signaling.Our results indicated that the logistic regression model based on LCAT,TNM stage and the serum level of α-fetoprotein in HCC patients could effectively predict high metastatic risk HCC patients.CONCLUSION LCAT is downregulated at translational and protein levels in HCC and might inhibit tumor metastasis via attenuating PI3K/AKT/mTOR signaling.LCAT is a prognostic marker and potential therapeutic target for HCC.

The Ebola epidemic is ongoing in West Africa and responses from China are positive

The ongoing Ebola outbreak poses an alarming risk to the countries of West Africa and beyond. On August 8, 2014, the World Health Organization(WHO) declared the cross-country Ebola outbreak a Public Emergency of International Concern. China has had no confirmed cases of Ebola. In this paper, virologic characteristics, pathogenesis, clinical manifestations, laboratory examination and prophylactic vaccines and therapeutic drugs of Ebola are summarized. Importantly, active responses and actions from China are introduced. Moreover, the key issues in the future prevention and control of Ebola were also addressed.

RNA binding protein TIAR modulates HBV replication by tipping the balance of pgRNA translation

The pregenomic RNA(pgRNA)of hepatitis B virus(HBV)serves not only as a bicistronic message RNA to translate core protein(Cp)and DNA polymerase(Pol),but also as the template for reverse transcriptional replication of viral DNA upon packaging into nucleocapsid.Although it is well known that pgRNA translates much more Cp than Pol,the molecular mechanism underlying the regulation of Cp and Pol translation efficiency from pgRNA remains elusive.

Cellular gp96 upregulates AFP expression by blocking NR5A2 SUMOylation and ubiquitination in hepatocellular carcinoma

Alpha-fetoprotein (AFP) is the most widely used biomarker for the diagnosis of hepatocellular carcinoma (HCC). However, asubstantial proportion of HCC patients have either normal or marginally increased AFP levels in serum, and the underlyingmechanisms are not fully understood. In the present study, we provided in vitro and in vivo evidence that heat shock protein gp96promoted AFP expression at the transcriptional level in HCC. NR5A2 was identified as a key transcription factor for the AFP gene, andits stability was enhanced by gp96. A further mechanistic study by co-immunoprecipitation, GST pull-down, and molecular dockingshowed gp96 and the SUMO E3 ligase RanBP2 competitively binding to NR5A2 at the sites spanning from aa 507 to aa 539. Thebinding of gp96 inhibited SUMOylation, ubiquitination, and subsequent degradation of NR5A2. In addition, clinical analysis of HCCpatients indicated that gp96 expression in tumors was positively correlated with serum AFP levels. Therefore, our study uncovered anovel mechanism that gp96 regulates the stability of its client proteins by directly affecting their SUMOylation and ubiquitination.These findings will help in designing more accurate AFP-based HCC diagnosis and progression monitoring approaches.

Integration of Prealbumin into Child-Pugh Classification Improves Prognosis Predicting Accuracy in HCC Patients Considering Curative Surgery

Background and Aims:The poor outcomes of hepatocellular carcinoma(HCC)patients may be due to not only malignant tumors but also limited liver function.Therefore,as stated in major guidelines,only patients with relatively normal liver function(Child-Pugh A)would be referred for curative hepatectomy.Even so,the postsurgery survival rate of patients is still extremely poor.Direct curative resection may benefit most patients.This study aimed to improve the prognosis predicting accuracy of the Child-Pugh scoring system.Methods:This study included two cohorts:cohort A being composed of 613 HCC patients,with a 23-month median postsurgery follow-up time;and cohort B being composed of 554 tumor-free chronic liver disease patients.Kaplan-Meier test and Cox model were used for survival analysis.Independent-samples t test or one-way ANOVA was used to test the differences between different groups.Results:Serum prealbumin levels were found inversely correlated with worsening of flbrotic scores(r=-0.482,p<0.001).Lower levels of presurgery prealbumin was an independent factor of poor postsurgery prognosis in Child-Pugh A patients,with a hazard ratio of 0.731(p=0.001).By integrating prealbumin together with total bilirubin level,serum albumin concentration and prothrombin time,a modified liver disease prognosis scoring system was developed to define traditional Child-Pugh A HCC patients as Modified Child-Pugh MCP-1,MCP-2 and MCP-3,with median postsurgery overall survival times of 44.00,28.00 and 11.00 months respectively.Conclusions:Preoperative serum prealbumin is a valuable prognosis predicting biomarker for Child-Pugh A HCC patients who may be under consideration for curative resection.With serum prealbumin included as one of the parameters,the MCP scoring system might improve the postsurgery survival predicting accuracy for HCC patients.

Liver Stiffness Measurement Can Reflect the Active Liver Necroinflammation in Population with Chronic Liver Disease:A Real-world Evidence Study

Background and Aims: Non-invasive evaluation of liver nec-roinflammation in patients with chronic liver disease is an un-met need in clinical practice.The diagnostic accuracy of transient elastography-based liver stiffness measurement(LSM)for liver fibrosis could be affected by liver necroinflam-mation,the latter of which could intensify stiffness of the liver.Such results have prompted us to explore the diagnosis potential of LSM for liver inflammation.Methods: Three cross-sectional cohorts of liver biopsy-proven chronic liver dis-ease patients were enrolled,including 1417 chronic hepatitis B(CHB)patients from 10 different medical centers,106 non-al-coholic steatohepatitis patients,and 143 patients with auto-immune-related liver diseases.Another longitudinal cohort of 14 entecavir treatment patients was also included.The re-ceiver operating characteristic(ROC)curve was employed to explore the diagnostic value of LSM.Results: In CHB patients,LSM value ascended with the increased severity of liver nec-roinflammation in patients with the same fibrosis stage.Such positive correlation between LSM and liver necroinflammation was also found in non-alcoholic steatohepatitis and autoim-mune-related liver diseases populations.Furthermore,the ROC curve exhibited that LSM could identify moderate and se-vere inflammation in CHB patients(area under the ROC curve as 0.779 and 0.838)and in non-alcoholic steatohepatitis pa-tients(area under the ROC curve as 0.826 and 0.871),respec-tively.Such moderate diagnostic value was also found in autoimmune-related liver diseases patients.In addition,in the longitudinal entecavir treated CHB cohort,a decline of LSM values was observed in parallel with the control of inflam-matory activity in liver.Conclusions: Our study implicates a diagnostic potential of LSM to evaluate the severity of liver necroinflammation in chronic liver disease patients.