HOOK1 Inhibits the Progression of Renal Cell Carcinoma via TGF-ß and TNFSF13B/VEGF-A Axis.

Accumulating evidence shows HOOK1 disordered in human malignancies. However, the clinicopathological and biological significance of HOOK1 in renal cell carcinoma (RCC) remains rarely studied. In this study, the authors demonstrate that HOOK1 is downregulated in RCC samples with predicted poorer clinical prognosis. Mechanistically, HOOK1 inhibits tumor growth and metastasis via canonical TGF-ß/ALK5/p-Smad3 and non-canonical TGF-ß/MEK/ERK/c-Myc pathway. At the same time, HOOK1 inhibits RCC angiogenesis and sunitinib resistance by promoting degradation of TNFSF13B through the ubiquitin-proteasome pathway. In addition, HOOK1 is transcriptionally regulated by nuclear factor E2F3 in VHL dependent manner. Notably, an agonist of HOOK1, meletin, is screened and it shows antitumor activity more effectively when combined with sunitinib or nivolumab than it is used alone. The findings reveal a pivotal role of HOOK1 in anti-cancer treatment, and identify a novel therapeutic strategy for renal cell carcinoma.

A novel 16-gene alternative mRNA splicing signature predicts tumor relapse and indicates immune activity in stage I-III hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is a lethal disease with high relapse and dismal survival rates. Alternative splicing (AS) plays a crucial role in tumor progression. Herein, we aim to integratedly analyze the relapse-associated AS events and construct a signature predicting tumor relapse in stage I-III HCC. Methods: AS events of stage I-III HCC with tumor relapse or long-term relapse-free survival were profiled to identify the relapse-associated AS events. A splicing network was set up to analyze the correlation between the relapse-associated AS events and splicing factors. Cox regression analysis and receiver operating characteristic curve were performed to develop and validate the relapse-predictive AS signature. Single-sample gene set enrichment analysis (ssGSEA) and the ESTIMATE algorithm were used to assess the immune infiltration status of the HCC microenvironment between different risk subgroups. Unsupervised cluster analysis was conducted to assess the relationship between molecular subtypes and local immune status and clinicopathological features. Results: In total, 2441 ASs derived from 1634 mRNA were identified as relapse-associated AS events. By analyzing the proteins involved in the relapse-associated AS events, 1573 proteins with 11590 interactions were included in the protein-protein interaction (PPI) network. In total, 16 splicing factors and 61 relapse-associated AS events with 85 interactions were involved in the splicing network. The relevant genes involved in the PPI network and splicing network were also analyzed by Gene Ontology enrichment analysis. Finally, we established a robust 16-gene AS signature for predicting tumor relapse in stage I-III HCC with considerable AUC values in all of the training cohort, testing cohort, and entire cohort. The ssGSEA and ESTIMATE analyses showed that the AS signature was significantly associated with the immune status of the HCC microenvironment. Moreover, four molecular subgroups with distinguishing tumor relapse modes and local immune status were also revealed. Conclusion: Our study built a novel 16-gene AS signature that robustly predicts tumor relapse and indicates immune activity in stage I-III HCC, which may facilitate the deep mining of the mechanisms associated with tumor relapse and tumor immunity and the development of novel individualized treatment targets for HCC.

A novel preoperative predictive model of 90-day mortality after liver resection for huge hepatocellular carcinoma.

BACKGROUND: Hepatectomy for huge hepatocellular carcinoma (HCC) (diameter ≥10 cm) is characterized by high mortality. This study aimed to establish a preoperative model to evaluate the risk of postoperative 90-day mortality for huge HCC patients. METHODS: We retrospectively enrolled 1,127 consecutive patients and prospectively enrolled 93 patients with huge HCC who underwent hepatectomy (training cohort, n=798; validation cohort, n=329; prospective cohort, n=93) in our institute. Based on independent preoperative predictors of 90-day mortality, we established a logistic regression model and visualized the model by nomogram. RESULTS: The 90-day mortality rates were 9.6%, 9.2%, and 10.9% in the training, validation, and prospective cohort. The α-fetoprotein (AFP) level, the prealbumin levels, and the presence of portal vein tumor thrombosis (PVTT) were preoperative independent predictors of 90-day mortality. A logistic regression model, AFP-prealbumin-PVTT score (APP score), was subsequently established and showed good performance in predicting 90-day mortality (training cohort, AUC =0.87; validation cohort, AUC =0.91; prospective cohort, AUC =0.93). Using a cut-off of -1.96, the model could stratify patients into low risk (≤-1.96) and high risk (>-1.96) with different 90-day mortality rates (~30% vs. ~2%). Furthermore, the predictive performance for 90-day mortality and overall survival was significantly superior to the Child-Pugh score, the model of end-stage liver disease (MELD) score, and the albumin-bilirubin (ALBI) score. CONCLUSIONS: The APP score can precisely predict postoperative 90-day mortality as well as long-term survival for patients with huge HCC, assisting physician selection of suitable candidates for liver resection and improving the safety and efficacy of surgical treatment.

BRCA1-associated protein 1 serves as a tumor suppressor in hepatocellular carcinoma by deubiquitinating and stabilizing PTEN.

BRCA1-associated protein 1 (BAP1) or its mutants have been known to play critical regulatory roles in tumor biology, yet their role in hepatocellular carcinoma (HCC) remains largely unclear. In this study, we detected the mutations of all the exons of BAP1 in 105 HCC patients using Sanger sequencing, and found eight somatic mutations in 6 (5.71%) patients. We also found that the mRNA and protein levels of BAP1 were markedly downregulated in HCC versus the adjacent non-tumor tissues. Wild-type BAP1 but not mutant BAP1 significantly inhibited HCC cell proliferation, invasion, epithelial-mesenchymal transition (EMT) in vitro, and tumor progression and metastasis in vivo. Mechanistically, BAP1 complexed with PTEN and stabilized PTEN via deubiquitination and, furthermore, negatively regulated HCC cell EMT by deactivating the AKT/GSK-3ß/Snail pathway. However, those tumor-inhibitory effects of BAP1 were abolished by inactivating mutations. Clinically, low BAP1 expression was positively correlated to aggressive tumor phenotypes, which also independently associated with poorer recurrence-free survival and overall survival after curative hepatectomy. Conclusively, our results indicate that BAP1, significantly downregulated, somatically mutated and negatively regulating EMT in HCC, serves as a tumor suppressor of HCC by deubiquitinating and stabilizing PTEN.

Effects of TACE combined with microwave ablation on T lymphocyte subsets and prognosis in patients with liver cancer and analysis of safety.

PURPOSE: To explore the influence of transcatheter hepatic arterial chemoembolization (TACE) combined with microwave ablation on T lymphocyte subsets and prognosis in patients with liver cancer and analyze the safety. METHODS: The clinical data of 160 patients were retrospectively analyzed. The patients in the control group underwent TACE, while those in the observation group were treated with microwave ablation in addition to TACE. Then, the changes in the levels of T lymphocyte subsets, liver function indexes and alpha-fetoprotein (AFP) before and after treatment were compared between the two groups. RESULTS: After treatment, the levels of cluster of differentiation 3+ (CD3+), CD4+ and CD4+/CD8+ of patients were significantly increased in both groups, while the levels of CD8+ and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and AFP were overtly lowered, while the observation group had more obvious changes in the above-mentioned levels (p<0.05). The response rate and prognostic survival rate were evidently higher in the observation group than in the control group (p<0.05). The complications after treatment showed no significant difference between the two groups (p>0.05). Child-Pugh, tumor diameter and number of lesions were independent risk factors for the prognosis of survival of liver cancer patients undergoing TACE combined with microwave ablation (p<0.05). CONCLUSIONS: TACE combined with microwave ablation has relatively high efficacy and safety in the treatment of liver cancer, which can improve liver function, immune function and prognostic survival.

BAP1 acts as a tumor suppressor in intrahepatic cholangiocarcinoma by modulating the ERK1/2 and JNK/c-Jun pathways.

Current therapeutic options for intrahepatic cholangiocarcinoma (ICC) are very limited, which is largely attributed to poor understanding of molecular pathogenesis of ICC. Breast cancer type 1 susceptibility protein-associated protein-1 (BAP1) has been reported to be a broad-spectrum tumor suppressor in many tumor types, yet its role in ICC remains unknown. The aim of this study was to investigate the clinical implications and biological function of BAP1 in ICC. Our results showed that the messenger RNA and protein levels of BAP1 were significantly downregulated in ICC versus paired non-tumor tissues. Overexpression of wild-type but not mutant BAP1 significantly suppressed ICC cell proliferation, cell cycle progression, and invasion in vitro, as well as tumor progression in vivo. Conversely, knockdown of BAP1 yielded opposing effects. Mechanistically, BAP1 functioned as a tumor suppressor in ICC by inhibiting the extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase/c-Jun pathways, and this function was abolished by inactivating mutations. Clinically, low BAP1 expression was positively correlated with aggressive tumor characteristics, such as larger tumor size, presence of lymphatic metastasis, and advanced tumor node metastasis stage. Survival analysis revealed that low BAP1 expression was significantly and independently associated with poor overall survival and relapse-free survival after curative surgery. In conclusion, BAP1 is a putative tumor suppressor of ICC, and may serve as a valuable prognostic biomarker as well as potential therapeutic target for ICC.

The effect of antiviral therapy on patients with hepatitis B virus-related hepatocellular carcinoma after curative resection: a systematic review and meta-analysis.

BACKGROUND AND AIM: Studies suggest that antiviral therapy performed after curative resection improves the postoperative prognosis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), but the evidence has been contradictory. The aim of this meta-analysis was to assess the effect of antiviral therapy with nucleoside analogs (NAs) after curative resection on the long-term postoperative survival of patients with HBV-related HCC. MATERIALS AND METHODS: MEDLINE, PubMed, Embase, and Cochrane Library were systematically searched up to August 2017 with no limits. Outcome measures were the primary parameter of overall survival (OS) after radical resection of HBV-related HCC and the secondary parameter of postoperative recurrence-free survival (RFS). RESULTS: A total of 9,009 patients (2,546 of whom received antiviral therapy and 6,463 received no treatment) were included. The pooled analysis revealed that antiviral therapy was associated with significantly improved OS (hazard ratio [HR]: 0.58; 95% confidence interval [CI]: 0.51-0.67; P<0.00001) and RFS (HR: 0.68; 95% CI: 0.63-0.74; P<0.00001). Moderate heterogeneity among studies for both OS and RFS was observed, which disappeared or decreased after pooling studies using one type of NA as antiviral drug. In the subgroup analysis, anti-viral therapy significantly prolonged both OS (HR: 0.69; 95% CI: 0.52-0.92; P=0.01) and RFS (HR: 0.58; 95% CI: 0.49-0.70; P<0.00001) in patients with high baseline HBV DNA level (≥20,000 IU/mL) with no heterogeneity, but not in patients with low baseline HBV DNA level (<20,000 IU/mL). CONCLUSION: Antiviral therapy with NAs confers significant survival benefits in patients with HBV-related HCC after curative resection, especially in patients with high baseline HBV DNA level (≥20,000 IU/mL).

Radiofrequency ablation versus surgical resection for intrahepatic hepatocellular carcinoma recurrence: a meta-analysis.

BACKGROUND: To compare the clinical efficacy and safety of radiofrequency ablation (RFA) versus surgical resection (SR) for intrahepatic hepatocellular carcinoma (HCC) recurrence by meta-analytical techniques. METHODS: Literature documenting a comparison of RFA and SR for intrahepatic HCC recurrence was identified by searching PubMed, Embase, Cochrane Library, and Web of Science databases, for those from inception to July 2014 with no limits. The heterogeneity was tested by the Cochrane Q statistic; the pooled estimates were measured using either fixed or random effect model. Furthermore, subgroup and sensitivity analyses were conducted to explore heterogeneity between studies and to assess the efficacy of different studies. RESULTS: Seven studies were included with a total of 718 patients (359 treated with RFA and 359 treated with SR). Our meta-analysis showed that the 1-, 3-, and 5-y overall survival rate and procedure-related mortality rate were similar in patients treated with RFA or SR. Meanwhile, SR was associated with significantly higher 1-, 3-, and 5-y re-recurrence-free survival rate and procedure-related morbidity rate compared with RFA. In the subgroup analysis of patients in China, the results concerning overall and re-recurrence-free survival were similar to the outcomes of the meta-analysis without regional restriction. In the subgroup analysis of intrahepatic recurrent HCC ≤3 cm, the 1-, 3-, and 5-y overall survival rate did not differ significantly in the comparison of RFA and SR. CONCLUSIONS: Although RFA was associated with lower re-recurrence-free survival, it seems to be as effective as SR for the treatment of intrahepatic HCC recurrence owing to comparable overall survival benefits. The advantages of being less invasive, highly target-selective, and repeatable may render RFA a preferred treatment option for selected patients.