Angiogenic Factor with G Patch and FHA Domains 1 (AGGF1) Acts as Diagnostic Biomarker and Adverse Prognostic Factor of Hepatocellular Carcinoma (HCC): Evidence from Bioinformatic Analysis.

BACKGROUND Angiogenic factor with G patch and FHA domains 1 (AGGF1) is a novel identified initiator of angiogenesis through promoting the proliferation of endothelial cells. The continuous angiogenesis plays a key role in the growth, invasion, and metastasis of hepatocellular carcinoma (HCC), while the diagnostic and prognostic roles of AGGF1 for HCC need to be further studied. MATERIAL AND METHODS The mRNA sequencing datasets and clinical features of HCC patients were extracted from The Cancer Genome Atlas database. The relationship between clinical features and AGGF1 expression was analyzed by Wilcoxon test. Further validation explorations were carried out using online database Oncomine. The diagnostic receiver operating characteristic curves of AGGF1 and alpha-fetoprotein were compared to examine the diagnostic efficacy of AGGF1. Survival analysis and Gene Set Enrichment Analysis were performed to explore the prediction value and potential mechanism of AGGF1 dysregulation in HCC. RESULTS Comprehensive overexpression of AGGF1 was observed in HCC, correlating with poor overall survival. Upregulated level of AGGF1 was statistically associated with poor differentiated histological grade, advanced cancer stage and T classification. AGGF1 was a more effective diagnostic marker than alpha-fetoprotein in HCC. Several important pathways related to HCC including pathway in cancer and P53 signaling pathway were differentially enriched in the high AGGF1 expression phenotype. CONCLUSIONS AGGF1 was a potential diagnostic and prognostic marker for poor clinical outcomes in HCC patients. Moreover, vital pathways regulated by AGGF1 in HCC may include regulation of autophagy, Wnt signaling pathway, pathway in cancer, cell cycle, and P53 signaling pathway.

Comparison of FIB-4 index, NAFLD fibrosis score and BARD score for prediction of advanced fibrosis in adult patients with non-alcoholic fatty liver disease: A meta-analysis study.

AIM: Non-alcoholic fatty liver disease (NAFLD)-related advanced hepatic fibrosis is associated with liver and cardiovascular morbidity and mortality. This study aims to compare the FIB-4 index, NAFLD fibrosis score (NFS) and BARD score for prediction of advanced liver fibrosis. METHODS: Pooled sensitivity, specificity, diagnostic odds ratio (DOR), summary receiver-operator curves (SROC) and Spearman's rank correlation coefficient were used to examine the accuracy of each non-invasive scoring system for predicting NAFLD-related advanced fibrosis. RESULTS: Four studies with 1038 adult patients were included in this meta-analysis. A total of 135 patients (13.0%) had advanced fibrosis. In the FIB-4 index group, pooled sensitivity and specificity with 95% confidence interval (CI), and the area under the ROC (AUROC) were 0.844 (0.772-0.901), 0.685 (0.654-0.716) and 0.8496 ± 0.0680, respectively, at a cut-off of 1.30. At a threshold of 3.25, the same parameters were 0.38 (0.30-0.47), 0.96 (0.95-0.98) and 0.8445 ± 0.0981. At a cut-off of -1.455, values were 0.77 (0.69-0.84), 0.70 (0.67-0.73) and 0.8355 ± 0.0667, respectively. At a 0.676 cut-off, pooled sensitivity and specificity with 95% CI were 0.27 (0.19-0.35) and 0.98 (0.96-0.98), respectively; and the AUROC was 0.647 ± 0.2208. In the BARD score group, pooled sensitivity and specificity with 95% CI were 0.74 (0.66-0.81) and 0.66 (0.63-0.69), respectively; and the AUROC was 0.7625 ± 0.0285. CONCLUSION: FIB-4 index with a 1.30 cut-off has better diagnostic accuracy than the FIB-4 index with a 3.25 cut-off, NFS and BARD score, despite showing its limited value for predicting NAFLD-related advanced fibrosis.

A Nomogram for Predicting Portal Hypertensive Gastropathy in Patients With Liver Cirrhosis: A Retrospective Analysis.

BACKGROUND: There is an urgent need for non-invasive methods for predicting portal hypertensive gastropathy (PHG). This study aims to develop and validate a non-invasive method based on clinical parameters for predicting PHG in patients with liver cirrhosis (LC). METHODS: The overall survival (OS) and hepatocellular carcinoma (HCC)-free survival were evaluated in LC patients, both with and without PHG. A prediction model for PHG was then constructed based on a training dataset that contained data on 492 LC patients. The discrimination, calibration, and clinical utility of the predicting nomogram were assessed using the C-index, calibration plot, and decision curve analysis. Internal validation was conducted using a bootstrapping method, and further external validation using data on the 208 other patients. RESULTS: LC patients with PHG had a worse prognosis compared with those without PHG. A nomogram was constructed using clinical parameters, such as age, hemoglobin content, platelet count and Child-Pugh class. The C-index was 0.773 (95% CI: 0.730-0.816) in the training cohort, 0.761 after bootstrapping and 0.745 (95% CI: 0.673-0.817) in the validation cohort. The AUC values were 0.767, 0.724, and 0.756 in the training, validation and total cohorts, respectively. Well-fitted calibration curves were observed in the training and validation cohorts. Decision curve analysis demonstrated that the nomogram was clinically useful at a threshold of 15%. CONCLUSION: The nomogram constructed to predict the risk of developing PHG was found to be clinically viable. Furthermore, PHG is an independent risk factor for OS of LC, but not for the occurrence of HCC.

Epigenetic restriction of Hippo signaling by MORC2 underlies stemness of hepatocellular carcinoma cells.

The evolutionarily conserved Hippo signaling pathway is a key regulator of stem cell self-renewal, differentiation, and organ size. While alterations in Hippo signaling are causally linked to uncontrolled cell growth and a broad range of malignancies, genetic mutations in the Hippo pathway are uncommon and it is unclear how the tumor suppressor function of the Hippo pathway is disrupted in human cancers. Here, we report a novel epigenetic mechanism of Hippo inactivation in the context of hepatocellular carcinoma (HCC). We identify a member of the microrchidia (MORC) protein family, MORC2, as an inhibitor of the Hippo pathway by controlling upstream Hippo regulators, neurofibromatosis 2 (NF2) and kidney and brain protein (KIBRA). Mechanistically, MORC2 forms a complex with DNA methyltransferase 3A (DNMT3A) at the promoters of NF2 and KIBRA, leading to their DNA hyper-methylation and transcriptional repression. As a result, NF2 and KIBRA are crucial targets of MORC2 to regulate confluence-induced activation of Hippo signaling and contact inhibition of cell growth under both physiological and pathological conditions. The MORC2-NF2/KIBRA axis is critical for maintaining self-renewal, sorafenib resistance, and oncogenicity of HCC cells in vitro and in nude mice. Furthermore, MORC2 expression is elevated in HCC tissues, associated with stem-like properties of cancer cells, and disease progression in patients. Collectively, MORC2 promotes cancer stemness and tumorigenesis by facilitating DNA methylation-dependent silencing of Hippo signaling and could be a potential molecular target for cancer therapeutics.

PKCδ silencing alleviates saturated fatty acid induced ER stress by enhancing SERCA activity.

Protein kinase C δ (PKCδ) plays an important role in nonalcoholic fatty liver disease (NAFLD), however, the mechanism remains unknown. The present study explored the role of PKCδ in NAFLD development and investigated the relationships between PKCδ, calcium homeostasis, and endoplasmic reticulum (ER) stress (ERS). Hepatic steatosis cell model was induced by palmitic acid (PA) in L02 cells. Lipid accretion was evaluated using Oil Red O staining and a triglyceride (TG) detection kit. PKCδ was down-regulated by siRNA. RT-PCR and Western blotting were used to detect the expression of ERS markers. The fluorescence of Ca2+ influx was recorded using confocal microscopy. Sarco-ER Ca2+-ATPase (SERCA) activity was measured by ultramicro-ATP enzyme test kit. PA treatment induced lipid accretion in L02 cells, destroyed the ER structure, and increased PKCδ activation in a time-dependent manner. Further, PA treatment significantly increased the expression of ERS markers, Ig heavy chain binding protein (Bip), and homologous proteins of CCAAT-enhancer binding proteins (CHOP). PKCδ silencing down-regulated Bip and CHOP expression, indicating a successful alleviation of ERS. The increased calcium storage induced by PA stimulation was significantly decreased in L02 cells treated with PKCδ siRNA compared with the negative control. Moreover, diminished SERCA activity caused by PA was recovered in PKCδ siRNA transfected cells. To the best of our knowledge, this is the first report demonstrating that the inhibition of PKCδ alleviates ERS by enhancing SERCA activity and stabilizing calcium homeostasis.

Rebamipide plus proton pump inhibitor versus proton pump inhibitor alone in the treatment of endoscopic submucosal dissection-induced gastric ulcer: a meta-analysis of randomized controlled trials.

Proton pump inhibitor (PPI) was the main prescription for gastric ulcer after endoscopic submucosal dissection (ESD). Some randomized controlled trials showed that a combination of rebamipide and PPI appears to be more efficient than PPI alone for the treatment of ESD-induced gastric ulcer. However, the sample sizes in these trials were limited and the conclusions were underpowered.This meta-analysis was conducted with 5 randomized controlled trials using the combination of rebamipide and PPI for healing ESD-induced ulcer compared with PPI monotherapy. Relevant studies were searched via MEDLINE, PubMed, Embase, and Cochrane Library databases by using terms such as "rebamipide," "proton pump inhibitor," "endoscopic submucosal dissection," "drug therapy," and "gastric ulcer or artificial ulcer."Five studies were included in this meta-analysis. The number of total patients was 626, with 317 patients in the combination group and 309 patients in the PPI alone group. The heterogeneity among these 5 studies was low (I = 22%, P = 0.28). All 5 studies considered scarring stage 1 rate as a primary endpoint, and the scarring stage 1 rate in combination group (115/317) was higher than that in PPI alone group (63/309) (odds ratio 2.61, 95% confidence interval [CI] 1.76-3.88). The mean difference of initial ulcer size between 2 groups was -4.46 (95% CI -266.61 to -257.69, P = 0.97), but it enlarged to 68.38 (95% CI 35.72-101.05, P < 0.00001) in the 4th week.This meta-analysis demonstrates that combination therapy is more efficient than PPI monotherapy in healing ESD-induced gastric ulcer.