UBE2O reduces the effectiveness of interferon-α via degradation of IFIT3 in hepatocellular carcinoma.

Interferon (IFN) exerts its effects through interferon-stimulated genes (ISGs), but its efficacy is limited by interferon resistance, which can be caused by the ubiquitination of key proteins. UBE2O was initially identified as a promising therapeutic target based on data from the TCGA and iUUCD 2.0 databases. Through the inhibition of UBE2O, interferon α/ß signaling and overall interferon signaling were activated. Integrating data from proteomic, mass spectrometry, and survival analyses led to the identification of IFIT3, a mediator of interferon signaling, as a ubiquitination substrate of UBE2O. The results of in vitro and in vivo experiments demonstrated that the knockdown of UBE2O can enhance the efficacy of interferon-α by upregulating IFIT3 expression. K236 was identified as a ubiquitination site in IFIT3, and the results of rescue experiments confirmed that the effect of UBE2O on interferon-α sensitivity is dependent on IFIT3 activity. ATO treatment inhibited UBE2O and increased IFIT3 expression, thereby increasing the effectiveness of interferon-α. In conclusion, these findings suggest that UBE2O worsens the therapeutic effect of interferon-α by targeting IFIT3 for ubiquitination and degradation.

Knockdown of AGGF1 inhibits the invasion and migration of gastric cancer via epithelial-mesenchymal transition through Wnt/ß-catenin pathway.

BACKGROUND: Angiogenic factor with G-patch and FHA domain 1 (AGGF1), as a newly identified human angiogenic factor, is overexpressed in some types of malignant tumors and closely associated with patient's prognosis. However, the mechanisms involved in the regulation of AGGF1 in gastric cancer (GC) still remain unclear. METHODS: In this study, AGGF1 level in GC tissues and cell lines was analyzed by western blot and quantitative real-time polymerase chain reaction (qRT-PCR). After knockdown of AGGF expression by RNA interference in GC cell lines MKN-45 and MGC-803, wound healing and transwell assays were conducted to examine the effects of AGGF1 on migration and invasion. Tumor growth was assessed in a mouse xenograft model in vivo. Furthermore, expression levels of epithelial-mesenchymal transition (EMT) biomarkers and involvement of the Wnt/ß-catenin pathway were detected by western blot and qRT-PCR. RESULTS: Compared to those in normal groups, the protein and mRNA of AGGF1 expression levels were significantly higher both in GC tissues and cell lines (all P < 0.05). Knockdown of AGGF1 dramatically inhibited the invasion and migration of MKN-45 and MGC-803 cells (all P < 0.01) in vitro, and suppressed the tumor growth of nude mice xenograft model in vivo. Western blot revealed alterations in EMT biomarkers, suggesting the role of AGGF1 in EMT. Moreover, we found that downregulated expression of AGGF1 attenuated Wnt/ß-catenin related protein expression. CONCLUSIONS: Collectively, knockdown of AGGF1 inhibits the invasion and migration of gastric cancer via epithelial-mesenchymal transition through Wnt/ß-catenin pathway.

Comprehensive analysis of aberrantly expressed profiles of lncRNAs, miRNAs and mRNAs with associated ceRNA network in cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a highly malignant and poorly differentiated bile duct cancer with an extremely poor prognosis, but the pathogenesis of CCA remains not well-known. Attention has been increasingly focused on long noncoding RNAs, which plays an important role in tumorigenesis. However, the roles of cancer specific lncRNA and its related competitive endogenous RNAs (ceRNA) network in CCA remain elusive. In this study, we comprehensively integrated expression profiles, including data on mRNAs, lncRNAs and miRNAs obtained from 36 CCA tissues and 9 normal tissues in The Cancer Genome Atlas. 1434 cancer specific lncRNAs, 68 miRNAs and 3538 mRNAs (|logFC|> 1, p< 0.05) were identified. Based on bioinformatics generated from miRcode, starBase, miRTarBase, TargetScan and miRDB, we constructed an lncRNA-miRNA-mRNA network (ceRNA network) in CCA. We constructed the lncRNA-miRNA-mRNA ceRNA network consisting of 206 molecules and 454 interactions. In addition, we used Cytoscape software to visualize the ceRNA network in WGCNA, 22 mRNA network modules were identified, five of which were significantly related to tumor grade and survival time. Moreover, three lncRNAs COL18A1-AS1, SLC6A1-AS1 and HULC were found to be significantly associated with overall survival. The present study provides novel insight for better understanding of lncRNA-related ceRNA network in CCA and useful resource for identifcation of novel biomarkers of CCA.

Martrilin-3 (MATN3) Overexpression in Gastric Adenocarcinoma and its Prognostic Significance.

BACKGROUND The aim of this study was to investigate the expression level of martrilin-3 (MATN3) in patients with gastric adenocarcinoma (GAC) and to investigate the prognostic significance of MATN3. MATERIAL AND METHODS Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) data were used to predict the expression and prognostic value of MATN3 mRNA in GAC patients. Seventy-six GAC patients had GAC tissue samples and paired adjacent normal tissue samples collected retrospectively to examine the MATN3 protein expression level by immunohistochemical staining. Furthermore, Kaplan-Meier univariate and Cox multivariate analyses were used to verify the correlation between MATN3 expression and clinicopathological parameters of GAC patients and the prognostic significance of MATN3. RESULTS The GEO and TCGA data predicted that MATN3 mRNA levels were significantly higher in GAC tissue compared to normal tissue (all p<0.05). Further survival analyses showed that GAC patients with high mRNA expression of MATN3 had significantly lower disease-free survival (DFS) and overall survival (OS) time than those with low mRNA expression of MATN3 (all p<0.05). Subsequent immunohistochemical staining results confirmed that the MATN3 protein levels in GAC tissues were highly expressed (p=0.000) compared to normal tissues. In addition, GAC patients with high protein expression of MATN3 had remarkably decreased OS compared to patients with low protein expression of MATN3 (p=0.000). Univariate and multivariate survival analyses revealed that MATN3 high expression could be used as an independent predictor of poor prognosis in GAC patients (all p=0.000). CONCLUSIONS This study confirmed that MATN3 protein was highly expressed in GAC patients, and MATN3 overexpression could be used as an independent predictor of poor prognosis in GAC patients.

High Expression of Angiogenic Factor with G-Patch and FHA Domain1 (AGGF1) Predicts Poor Prognosis in Gastric Cancer.

BACKGROUND Angiogenic factor with G-patch and FHA domain1 (AGGF1 or VG5Q) is a newly identified human angiogenic factor. The aim of this study was to explore AGGF1 expression level in gastric cancer and detect its correlation with the prognosis. MATERIAL AND METHODS Immunohistochemistry was performed to detect AGGF1 level in gastric cancer and its adjacent noncancerous samples of 198 cases, and the relationships among the expression levels of AGGF1, vascular endothelial growth factor (VEGF), and prognosis were analyzed. RESULTS Expression of AGGF1 in gastric cancer samples was significantly higher than that in adjacent noncancerous samples (P<0.001). The overall survival rate (OS) of patients with high AGGF1 expression was significantly lower than that of patients with low AGGF1 expression (P=0.000). The Cox model analysis demonstrated that expression of AGGF1 was an independent biomarker for prediction of patients' survival in gastric cancer. CONCLUSIONS High expression of AGGF1 predicts poor prognosis in gastric cancer patients. AGGF1 can be used as an independent factor to predict postoperative survival of patients with gastric cancer.

Stromal Myofibroblasts Are Associated with Poor Prognosis in Solid Cancers: A Meta-Analysis of Published Studies.

OBJECTIVE: Published studies have evaluated the impact of stromal myofibroblasts on prognosis in solid cancers. However, the results of these studies remain controversial. We therefore performed a meta-analysis to address this issue. METHODS: The PubMed, ISI Web of Science and Embase databases were searched through November 30th, 2015 by two investigators, and a total of 17 studies that contained 2606 patients were included. Stromal myofibroblasts were quantified in solid cancers using α-smooth muscle actin staining. Pooled Odds Ratio with 95% Confidence Intervals were calculated, and publication bias was analyzed. RESULTS: The results of this study suggest that in solid cancers, a high density of stromal myofibroblasts is significantly associated with poor 3- and 5-year overall survival (pooled odds ratio (95% confidence interval): 1.33 (1.10-1.60) for 3-year overall survival and 1.68 (1.22-2.32) for 5-year overall survival). In addition, a high density of stromal myofibroblasts also predicted poor 3- and 5-year disease-free survival (1.30 (1.05-1.60) for 3-year disease-free survival and 1.36 (1.01-1.83) for 5-year disease-free survival). However, stromal myofibroblasts were not associated with 3- and 5-year cancer-specific survival. No publication bias was found for all analyses. CONCLUSIONS: The results of this study suggest that a high density of stromal myofibroblasts is associated with poor survival in solid cancers. More studies were required to investigate the prognostic value of stromal myofibroblasts in different types of solid cancers.

Nomogram to predict anastomotic leakage after laparoscopic anterior resection with intracorporeal rectal transection and double-stapling technique anastomosis for rectal cancer.

BACKGROUND/AIMS: Laparoscopic rectal cancer surgery involving rectal division with intracorporeal stapling devices is technically difficult. This study aimed to identify risk factors for anastomotic leakage associated with laparoscopic anterior resection for rectal cancer. METHODOLOGY: 476 patients who underwent laparoscopic anterior resection with intracorporeal rectal transection and double-stapling technique (DST) anastomosis for rectal cancer between July 2007 and February 2013 were retrospectively studied. All clinical variables were examined by univariate and multivariate analyses. A nomogram was developed to predict postoperative anastomotic leakage, given associated risk factors, and bootstrap validation was performed. The outcome of interest was clinical anastomotic leakage. RESULTS: In multivariate analysis, tumor location (p=0.001), operation time (p=0.001) and preservation of the left colic artery (p=0.037) were independently and significantly associated with anastomotic leakage. The resulting nomogram demonstrated good accuracy in predicting long-term complication, with a bootstrapcorrected concordance index 0.835. CONCLUSIONS: Our results suggest that we found that tumor localization, preservation of the left colic artery and operation time are predictive factors for clinical anastomotic leakage in laparoscopic anterior resection with intracorporeal rectal transection and double-stapling technique (DST) anastomosis for rectal cancer.

Analysis of risk factors for postoperative complication of repair of bile duct injury after laparoscopic cholecystectomy.

BACKGROUND: Bile duct injury (BDI) after laparoscopic cholecystectomy (LC-BDI) is still a major problem. However, despite the many improvements in clinical management of patients undergoing repair, postoperative complications remain frequent and factors that increase the susceptibility to such adverse events remain unknown. AIM: To report on a large experience with laparoscopic cholecystectomy-associated bile duct injuries (LC-BDIs) and define predictive factors associated with postoperative complication. METHODS: A retrospective medical record review of 94 patients referred for the surgical management of major BDIs to our center during a 12-year period between January 1, 1998, and December 31, 2010, was performed. Univariate statistical analysis and multivariate analysis were used to identify risk factors for postoperative complications. A nomogram was developed to predict postoperative complication, given associated risk factors, and bootstrap validation was performed. RESULTS: In univariate analysis, there is no factor significantly associated with short-term complication. There was a statistically significant relationship between type of repair and the risk of biliary strictures (p = 0.012). Other factors significantly associated with late biliary strictures were sepsis (p = 0.007) and bile leak (p = 0.003). In multivariate analysis, bile leak (p = 0.005), sepsis (p = 0.03), and type of repair (p = 0.028) were independently and significantly associated with long-term complication. The resulting nomogram demonstrated good accuracy in predicting long-term complication, with a bootstrap-corrected concordance index 0.7905. CONCLUSIONS: Our results suggest that missed injuries that result in sepsis or bile leak as well as high injuries that require hepaticojejunostomy will result in a higher stricture rate after repair.