Functional analysis of deubiquitylating enzymes in tumorigenesis and development

The ubiquitin system regulates diverse biological processes, many involved in cancer pathogenesis, by altering the ubiquitination state of protein substrates. This is accomplished by ubiquitin ligases and deubiquitinases (DUBs), which respectively add or remove ubiquitin from substrates to alter their stability, activity, localization and interactions. While lack of catalytic activity makes therapeutic targeting of ubiquitin ligases difficult, DUB inhibitors represent an active area of research and the identification of cancer-associated DUBs may lead to the development of novel therapeutics. A growing body of literature demonstrates that the DUB Otubain 1 (OTUB1) regulates many cancer-associated signaling pathways including MAPK, ERa, epithelial-mesenchymal transition (EMT), RHOa, mTORC1, FOXM1 and P53 to promote tumor cell survival, proliferation, invasiveness and therapeutic resistance. In addition, clinical studies have associated elevated OTUB1 expression with high grade, invasiveness and metastasis in several tumor types including lung, breast, ovarian, glioma, colon and gastric. Interestingly, in addition to catalytic DUB activity, OTUB1 displays a catalytic-independent, non-canonical activity where it inhibits the transfer of ubiquitin onto protein substrates by sequestration of E2 ubiquitin-conjugating enzymes. The aim of this review is to describe the canonical and non-canonical activities of OTUB1, summarize roles for OTUB1 in cancer-associated pathways and discuss its potential therapeutic targeting.

/pdf/otubain-1-a-non-canonical-deubiquitinase-with-an-emerging-3udr4wunte.pdf

Otubain 1: a non-canonical deubiquitinase with an emerging role in cancer.

Deubiquitination of MYC by OTUB1 contributes to HK2 mediated glycolysis and breast tumorigenesis

Meta-analysis of laparoscopic versus open liver resection for hepatocellular carcinoma.

Several studies have been conducted comparing laparoscopic liver resection (LLR) versus open liver resection (OLR) for hepatocellular carcinoma (HCC), however, the optimal therapeutic approach has not been established. Therefore, we conducted a systematic review and meta-analysis of studies comparing LLR versus OLR for HCC. MEDLINE and Cochrane Central Register of Controlled Trials database were systematically searched for relevant studies. Fifty-one studies were identified including a total of 6812 patients (2786 patients underwent LLR and 4026 patients were subjected to OLR). Blood transfusion rate, hospital stay in days, 30-days mortality rate and morbidity were significantly lower in LLR comparing with OLR (odds ratio (OR) 0.45; 95% confidence interval (CI) 0.30–0.69; P = 0.001; I2 = 55.83%), (MD − 3.87; 95% CI − 4.86 to − 2.89; P = 0.001; I2 = 87.35%), (OR 0.32; 95% CI 0.16–0.66; P = 0.001; I2 = 0%), and (OR 0.42; 95% CI 0.34–0.52; P = 0.001; I2 = 39.64), respectively. There was no significant difference between LLR and OLR regarding the operative time in minutes, resection margin in centimeter and R0 resection (MD 18.29; 95% CI − 1.58 to 38.15; p = 0.07; I2 = 91.73%), (MD 0.04; 95% CI − 0.06 to 0.14; P = 0.41; I2 = 48.03%) and (OR 1.31; 95% CI 0.98–1.76; P = 0.07; I2 = 0%), respectively. The 1-year overall survival (1-OS) and 5-OS rates were significantly higher in LLR comparing with OLR (OR 1.45; 95% CI 1.06–1.99; P = 0.02; I2 = 25.59%) and (OR 1.36; 95% CI 1.07–1.72; P = 0.01; I2 = 14.88%), respectively. LLR is superior to OLR regarding intraoperative blood loss, blood transfusion rate, hospital stay in days, 30-days mortality and morbidity, however, randomized controlled trials are needed to identify the superiority of either strategy.

Open versus laparoscopic hepatic resection for hepatocellular carcinoma: a systematic review and meta-analysis

OTUB1 (OTU domain-containing ubiquitin aldehyde binding protein 1) is a deubiquitinating enzyme (DUB) that belongs to the ovarian tumor (OTU) domain protease superfamily Although it has been demonstrated to play important roles in the development of many kinds of cancer, the mechanism of OTUB1 in hepatocellular carcinoma (HCC) is not clear The aim of this study was to explore the roles of OTUB1 in HCC progression using cell lines and 115 archived HCC samples In addition, the clinical outcomes were also analyzed with a special focus on OTUB1 expression in HCC samples In the immunohistochemical study, OTUB1 showed high expression in 60 of the 115 cases (522%) The OTUB1 expression level was significantly correlated with many clinicopathological parameters, including TNM stage (P = 0002), histology stage (P = 0002), and metastasis/recurrence (P = 0016) Survival analysis showed that the group with OTUB1 overexpression had significantly shorter overall survival time than the group with OTUB1 downregulation (hazard ratio [HR] = 0482; confidence interval [CI]: 0311-0748; P = 0001) Multivariate analysis indicated that OTUB1 expression was a significant and independent prognostic parameter (HR = 0214; CI: 0126-0364; P < 0001) for HCC patients The ability of HCC cells to undergo proliferation, migration, and invasion was suppressed by disruption of endogenous OTUB1 using short hairpin RNA (shRNA) OTUB1 expression appears to be a new and independent predictor for the prognosis of HCC patients Overexpression of OTUB1 in HCC could be a novel, effective, and supplementary biomarker for HCC because it plays a vital role in the progression of HCC

/pdf/expression-of-otub1-in-hepatocellular-carcinoma-and-its-23lm1op31k.pdf

Expression of OTUB1 in hepatocellular carcinoma and its effects on HCC cell migration and invasion.

Purpose: To investigate the risk factors for recurrence and treatment strategies after patients with hepatocellular carcinoma (HCC) undergo total laparoscopic hepatectomy (LH). Methods: The study included 109 patients who underwent LH (laparoscopy resection [LR] group, n = 50) or open hepatectomy [OH] (open resection [OR] group, n = 59) for HCC in our hospital between March 2011 and June 2016. Perioperative outcomes, disease recurrence, survival, and risk factors for recurrence were analyzed. Results: Patient characteristics did not significantly differ between groups. The 1- and 3-year survival rates were 90.7% and 78.1%, respectively, for the LR group and 83.1% and 74.4%, respectively, for the OR group (P = .71). The 1- and 3-year disease-free survival rates were 89.6% and 51.4%, respectively, for the LR group and 84.7% and 59.6%, respectively, for the OR group (P = .935). Tumor size, differentiation, vascular invasion, surgical bleeding, and surgical resection margin were risk factors for tumo...

/pdf/recurrence-of-hepatocellular-carcinoma-after-laparoscopic-4bqemvbyyy.pdf

Recurrence of Hepatocellular Carcinoma After Laparoscopic Hepatectomy: Risk Factors and Treatment Strategies.

Background Circular RNAs (circRNAs), a novel type of non-coding RNA, play a vital role in the pathogenesis and development of cancer. CircRNAs signatures may be useful as prognostic and predictive factors as well as clinical tools for evaluating disease status and prognosis. This study was carried out to explore novel circRNA signatures in hepatocellular carcinoma (HCC). Methods The expression profiles of circRNAs were retrieved from the Gene Expression Omnibus (GEO). The expression profiles of miRNAs and mRNAs were obtained from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) database. The results of the microarray were validated by quantitative real-time RCR (qPCR). Based on circRNA-miRNA pairs and miRNA-mRNA pairs, a competitive endogenous RNA (ceRNA) network was constructed. Functional analysis was performed via Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), and gene set variation analysis (GSVA). Furthermore, survival analysis was carried out using the Kaplan-Meier curve and the log-rank test. Results Differentially expressed circRNAs in HCC from GEO databases (GSE94508 and GSE97332) were screened and analyzed using the bioinformatics method. We detected a total of 26 differentially expressed circRNAs by qPCR and then selected 6 circRNAs to construct the circRNA-miRNA-mRNA networks. Through prognostic analysis, 3 target hub genes (AURKA, KIF5B, and RHOA) of circRNAs were discovered. Moreover, GSEA and GSVA were used to reveal the functions of AURKA, KIF5B, and RHOA in HCC. Conclusions We identified three hub genes, and our results suggest that the circHMGCS1/miR-581/AURKA, circHMGCS1/miR-892a/KIF5B, and circTMCO3/miR-577/RHOA axes may play a vital role in HCC progression.

/pdf/identification-and-integrated-analysis-of-hepatocellular-3i186jx2qk.pdf

Identification and integrated analysis of hepatocellular carcinoma-related circular RNA signature

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Expression of OTUB1 in hepatocellular carcinoma and its effects on HCC cell migration and invasion.

Recurrence of Hepatocellular Carcinoma After Laparoscopic Hepatectomy: Risk Factors and Treatment Strategies.

Identification and integrated analysis of hepatocellular carcinoma-related circular RNA signature