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Background: Patients with hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) present a poor prognosis. Current systemic therapies offer limited benefits. Hepatic artery infusion chemotherapy (HAIC) is a local regional treatment for advanced HCC, particularly in selected patients such as patients with PVTT or high intrahepatic tumor burden. Objectives: The purpose of this study is to retrospectively evaluate the efficacy and safety of HAIC combined with anti-PD-1 immunotherapy for HCC patients with PVTT, and explore factors related to survival prognosis, providing clues for treatment decisions for HCC patients. Design: This is a single-center retrospective study conducted over 2 years on consecutive PVTT patients receiving HAIC combined anti-PD-1 antibodies. Methods: The primary endpoint was overall survival (OS). Univariate and multivariate analyses were performed to identify prognostic factors affecting OS. Treatment-associated adverse events were evaluated as well. Results: A total of 119 patients were analyzed. The median OS and PFS were 14.9 months and 6.9 months. A total of 31.1% of grade 3–4 adverse events were reported, with elevated transaminase and total bilirubin being the most common. The independent variables correlated with survival include treatment-related alpha-fetoprotein (AFP) response, the presence of extrahepatic organ metastasis, absolute value of platelet (PLT), neutrophil-to-lymphocyte ratio, and combined usage of tyrosine kinase inhibitors (TKIs). Conclusion: In HCC patients with PVTT, combination therapy with HAIC and anti-PD-1 antibodies might be a promising therapy. The efficacy and safety of this combination protocol on patients with HCC complicated by PVTT warrants further investigation prospectively, especially in combination with TKIs. [ABSTRACT FROM AUTHOR]

Oxaliplatin is commonly used as the first‐line chemotherapeutic agent for advanced hepatocellular carcinoma (HCC). Unfortunately, the acquired resistance, limits the effectiveness of oxaliplatin and the underlying mechanisms remain unknown. Therefore, we explored the role of NOD‐like receptor protein 3 (NLRP3)/IL‐1β in mediating oxaliplatin resistance in HCC. We observed that NLRP3/IL‐1β expression was much higher in oxaliplatin‐resistant HCC cells. To further understand its impact on drug resistance, we knocked down NLRP3 and observed that it sensitized HCC cells to the growth‐inhibitory effects of oxaliplatin and induced cell apoptosis. NLRP3/IL‐1β overexpressing tumor cells also attracted polymorphonuclear myeloid‐derived suppressor cells. Using mouse models, we demonstrated that NLRP3/IL‐1β inhibition by short hairpin RNA or MCC950 effectively overcame oxaliplatin resistance. Furthermore, NLRP3/IL‐1β inhibition resulted in reduced expression of PD‐L1. We also found that PD‐L1 antibody combined with NLRP3/IL‐1β blockade displayed significant antitumor effect in HCC. Overall, our study provides compelling evidence supporting the essential role of NLRP3/IL‐1β in conferring resistance to oxaliplatin and reshaping the immunosuppressive microenvironment in HCC. Targeting NLRP3/IL‐1β presents a potential therapeutic target for overcoming oxaliplatin resistance and reshaping microenvironment of HCC. [ABSTRACT FROM AUTHOR]

The poliovirus receptor (PVR) is a member of the immunoglobulin superfamily (Ig SF) and is essential for the promotion of cancer cell proliferation and invasion. However, the correlation between PVR expression and prognosis as well as immune infiltration in hepatocellular carcinoma (HCC) remains unclear. The expression level of PVR was quantified using the Tumor and Tumor Immunity Evaluation Resource (TIMER) and Sangerbox. The Gene Expression Omnibus (GEO) database was used to validate the PVR expression. The receiver operating characteristic (ROC) curve was used to evaluate the feasibility of using PVR as a differentiating factor according to the area under curve (AUC) score. A PVR binding protein network was built using the STRING tool. An enrichment analysis using the R package clusterProfiler was used to explore the potential function of PVR. Immune infiltration analysis was calculated with ESTIMATE algorithms. We also assessed the correlation between PVR expression and immune infiltration by the single-sample Gene Set Enrichment Analysis (ssGSEA) method from the R package GSVA and TIMER database. The results showed that PVR was commonly overexpressed in multiple types of tumors including HCC. The data of GSE64041 confirmed the same result. The ROC curve suggested that PVR could be a potential diagnostic biomarker. Additionally, high mRNA expression of PVR in HCC was significantly correlated with poor overall survival (OS) and relapse free survival (RFS). Results also indicated correlations between PVR mRNA expression with the level of infiltration immune cells including B cells, CD8+ T cells, cytotoxic cells, DCs, CD56dim NK cells, pDCs, and Th2 cells. Furthermore, the PVR level was significantly correlated with immune markers for immunosuppressive cells in HCC. In conclusion, PVR might be an important regulator of tumor immune cell infiltration and a valuable prognostic biomarker in HCC. However, additional work is needed to fully elucidate the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Background: The spontaneous rupture of hepatocellular carcinoma (HCC) is associated with high mortality rates, and liver resection can provide better outcomes than other available treatments. However, the survival length of patients subjected to hepatectomy after spontaneous rupture of hepatocellular carcinoma remains controversial. Method: Articles reporting the comparison of the survival outcome between patients with rupture HCC (rHCC) and non-rupture HCC (nrHCC) from the inception until December 31, 2021 by PubMed, Web of Science, OVID, and the Cochrane Library databases were included. The high-quality propensity score matching analysis was used to investigate the impact of rupture on disease-free survival (DFS) and overall survival (OS) between the rHCC and nrHCC group with no heterogeneity. Result: A total of 606 patients from six cohort studies were included. The major baseline characteristics of the eligible patients were well balanced between rHCC and nrHCC group. The 1-, 3-, and 5-year hazard ratios of DFS were 3.45 (95% confidence interval [CI] 2.54–4.68), 3.63 (95% CI 2.87–4.60), and 3.72 (95% CI 2.93–4.72), respectively. The 1-, 3-, and 5-year hazard ratios of OS were 5.01 (95% CI 3.26–7.69), 5.49 (95% CI 4.08–7.39), and 4.20 (95% CI 3.20–5.51), respectively. Conclusion: The present meta-analysis demonstrated that the DSF and OS were significantly shorter in the rHCC group than in the nrHCC group, thus revealing that spontaneous HCC rupture was a predictor of poor survival. [ABSTRACT FROM AUTHOR]

Introduction: TRIpartite motif (TRIM) proteins are important members of the Really Interesting New Gene‐finger‐containing E3 ubiquitin‐conjugating enzyme and are involved in the progression of hepatocellular carcinoma (HCC). However, the diverse expression patterns of TRIMs and their roles in prognosis and immune infiltrates in HCC have yet to be analyzed. Materials: Combined with previous research, we used an Oncomine database and the Human Protein Atlas to compare TRIM family genes' transcriptional levels between tumor samples and normal liver tissues, as verified by the Gene Expression Profiling Interactive Analysis database. We investigated the patient survival data of TRIMs from the Kaplan–Meier plotter database. Clinicopathologic characteristics associations and potential diagnostic and prognostic values were validated with clinical and expressional data collected from the cancer genome atlas. Results: We identified TRIM28, TRIM37, TRIM45, and TRIM59 as high‐priority members of the TRIMs family that modulates HCC. Low expression of TRIM28 was associated with shorter overall survival (OS) than high expression (log‐rank p = 0.009). The same trend was identified for TRIM37 (p = 0.001), TRIM45 (p = 0.013), and TRIM59 (p = 0.011). Multivariate analysis indicated that the level of TRIM37 was a significant independent prognostic factor for both OS (p = 0.043) and progression‐free interval (p = 0.044). We performed expression and mutation analysis and functional pathways and tumor immune infiltration analysis of the changes in TRIM factors. Conclusion: These data suggested that TRIM28, TRIM37, TRIM45, and TRIM59 could serve as efficient prognostic biomarkers and therapeutic targets in HCC. [ABSTRACT FROM AUTHOR]

Objective: Several new first-line treatments were recently approved for unresectable hepatocellular carcinoma (HCC). In this meta-analysis, we compare the efficacy and safety of first-line systemic treatments to provide information for clinical decision making in unresectable HCC. Methods: Pubmed, Science Direct, Web of Science, Scopus, Ovid MEDLINE, Embase, Google Scholar, the Cochrane Library, EMbase, CNKI, CBM, VIP, and the Wanfang databases, as well as the Cochrane Central Register of Controlled Trails were searched for randomized clinical trials evaluating the efficacy of first-line chemotherapy, molecular targeted therapy, or immunotherapy for unresectable HCC. Hazard ratios with 95% confidence intervals (CIs) were calculated to explore the effects of various treatment options on overall survival (OS) and progression-free survival (PFS), whereas odd ratios with 95% CIs were used for adverse events (AEs) and serious adverse events (SAEs). A network meta-analysis was performed to synthesize data and for direct and indirect comparisons between treatments. The cumulative ranking curve (SUCRA) and P score were used to rank treatments. The risk of bias across studies was assessed graphically and numerically using the funnel plot and Egger's regression test. Results: Fifteen studies including 9005 patients were analyzed. Sintilimab plus bevacizumab, atezolizumab plus bevacizumab, and donafenib had better OS outcomes than sorafenib. Sintilimab plus bevacizumab, atezolizumab plus bevacizumab, lenvatinib, and linifanib had better PFS outcomes than sorafenib. The results of network meta-analysis showed that sintilimab plus bevacizumab was associated with the best OS and PFS. Egger's tests indicated that none of the included studies had obvious publication deviation. Conclusion: Sintilimab plus bevacizumab showed the best OS and PFS outcomes with no additional AEs or SAEs. Thus, sintilimab plus bevacizumab may be a better first line choice for the treatment of patients with unresectable HCC. Systematic Review Registration: PROSPEROI [ https://www.crd.york.ac.uk/PROSPERO/index.php ], identifier CRD42021269734. [ABSTRACT FROM AUTHOR]

Albumin to gamma-glutamyltransferase ratio (AGR) is a newly developed biomarker for the prediction of patients' prognosis in solid tumors. The purpose of the study was to establish a novel AGR-based nomogram to predict tumor prognosis in patients with early-stage HCC undergoing radiofrequency ablation (RFA). 394 hepatocellular carcinoma (HCC) patients who had received RFA as initial treatment were classified into the training cohort and validation cohort. Independent prognostic factors were identified by univariate and multivariate analyses. The value of AGR was evaluated by the concordance index (C -index), receiver operating characteristic (ROC) curves, and likelihood ratio tests (LAT). Logistic regression and nomogram were performed to establish the pretreatment scoring model based on the clinical variables. As a result, AGR = 0.63 was identified as the best cutoff value to predict overall survival (OS) in the training cohort. According to the results of multivariate analysis, AGR was an independent indicator for OS and recurrence-free survival (RFS). In both training cohort and validation cohort, the high-AGR group showed better RFS and OS than the low-AGR group. What is more, the C -index, area under the ROC curves, and LAT χ 2 values suggested that AGR outperformed the Child-Pugh (CP) grade and albumin-bilirubin (ALBI) grade in terms of predicting OS. The AGR, AKP, and tumor size were used to establish the OS nomogram. Besides, the results of Hosmer-Lemeshow test and calibration curve analysis displayed that both nomograms in the training and validation cohorts performed well in terms of calibration. Therefore, the AGR-based nomogram can predict the postoperative prognosis of early HCC patients undergoing RFA. [ABSTRACT FROM AUTHOR]

Background: Nivolumab and pembrolizumab disrupt the programmed cell death-1 immune checkpoint and display promising efficacy and safety results in advanced hepatocellular carcinoma (HCC). However, the benefits remain limited. The preliminary results of lenvatinib (LEN) combined with immune checkpoint inhibitors (ICIs) reveal that the combinations were well-tolerated and encouraging. This study aimed to analyze the safety and efficacy of LEN plus ICIs in a real-world cohort of patients with advanced HCC. Method: Between June 4, 2017, and June 30, 2019, 16 patients received LEN plus nivolumab, and 13 patients were treated with LEN plus pembrolizumab, with the confirmed advanced HCC retrospectively analyzed. The clinical parameters, as well as the outcomes, were assessed. Results: All the patients had Barcelona Clinical Liver Cancer Stage C. LEN with ICIs was used as systemic second-, third-, and fourth-line treatments in seven (24.1%), 14 (48.3%), and eight (27.6%) patients, respectively. At the time of data cutoff, six patients (37.5%) were still receiving LEN with nivolumab, while another six patients (46.2%) were still receiving LEN with pembrolizumab. An objective response was recorded in seven patients (25.9%), while the best overall responses were from one complete response and six partial responses. The 6- and 12-month over survival (OS) rates were 62.6% and 53.7%, respectively. Furthermore, the 6- and 12-month progression-free survival (PFS) rates were 43.5% and 31.8%, respectively. In the subgroup analyses, the 6- and 12-month OS and PFS rates for patients treated with LEN plus nivolumab were 62.5% and 52.1%, respectively, and 43.8% and 30.0%, respectively. The 6- and 12-month OS and PFS rates for patients treated with LEN plus pembrolizumab were 51.3% and 51.3%, respectively, and 49.2% and 49.2%, respectively. A total of 11 (31%) deaths were reported in this study, four of which were attributed to grade 5 adverse events presented as fatal treatment-related hepatitis. Conclusion: The combination of LEN and ICIs is a promising new strategy for the treatment of HCC patients. However, high-grade hepatic toxicity was observed and further evaluation of this combination is still required. [ABSTRACT FROM AUTHOR]

Background: Patients with hepatocellular carcinoma (HCC) with main portal vein tumor thrombus (mPVTT) have poor prognosis. Promising systemic therapies, such as target therapies, have limited benefits. The purpose of this study is to retrospectively evaluate the benefits of conventional TACE (c-TACE) and to establish a prognostic stratification of HCC patients with mPVTT. Methods: This is a single center retrospective study conducted over 5 years (duration of performing c-TACE), on consecutive HCC patients with mPVTT receiving c-TACE. Univariable and multivariable analysis were used to explore factors independently associated with overall survival (OS). Based on Cox-regression analysis, prognostic models were developed and internally validated by bootstrap methods. Discrimination and performance were measured by Akaike information criterion, concordance index, and likelihood ratio test. Results: A total of 173 patients were included. Median OS was 6.0 months (95%CI: 3.92~8.08). The independent variables correlated with survival were largest tumor diameter, tumor number, mPVTT extension, and AFP. In the final model, patients were assigned 2 points if largest tumor diameter ≥8 cm, or tumor number ≥2, 1point if main trunk was complete obstructed, or AFP ≥400 ng/ml. By summing up these points, patients were divided into three risk groups according to the score at the 15rd and 85th percentiles, in which median OS were 18, 7, and 3.5months, respectively (p<0.001). The model shown optimal discrimination, performance, and calibration. Conclusions: c-TACE could provide survival benefits in HCC patients with mPVTT and the proposed prognostic stratification may help to identify good candidates for the treatment, and those for whom c-TACE may be futile. [ABSTRACT FROM AUTHOR]

Background and Aim. With regard to patients with intermediate-stage, irresectable hepatocellular carcinoma (HCC), transcatheter arterial chemoembolization (TACE) is the mainstay of treatment. There is an urgent clinical requirement to identify reliable biomarkers to predict the response of HCC patients to TACE treatment. We aimed to identify a gene signature for predicting TACE response in HCC patients based on bioinformatics analysis. Methods. We downloaded the gene expression profile GSE104580 based on 147 tumor samples from 81 responders to TACE and 66 nonresponders from the Gene Expression Omnibus (GEO) database. Then, we randomly divided the 147 tumor samples into a training set (n = 89) and a validation set (n = 58) and screened differentially expressed genes (DEGs) in the training set. Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to annotate functions of the DEGs. The DEGs were mapped into the STRING website for constructing protein-protein interaction (PPI). The predictive value of the candidate genes by receiver-operating characteristic (ROC) curves was further verified in the validation set. Results. We totally found 158 DEGs (92 upregulated genes and 66 downregulated genes) in the training set. The GO enrichment analysis revealed that DEGs were significantly enriched in metabolic and catabolic processes, such as drug metabolic process, fatty acid metabolic process, and small molecule catabolic process. The KEGG pathway analysis revealed that the DEGs were mainly concentrated in drug metabolism-cytochrome P450, metabolism of xenobiotics by cytochrome P450, and chemical carcinogenesis. We identified 6 candidate genes (CXCL8, AFP, CYP1A1, MMP9, CYP3A4, and SERPINC1) based on the PPI network of the DEGs, which had high predictive value in HCC response to TACE with an area under the curve (AUC) value of 0.875 and 0.897 for the training set and validation set, respectively. Conclusion. We identified a six-gene signature which might be biomarkers for predicting HCC response to TACE by a comprehensive bioinformatics analysis. However, the actual functions of these genes required verification. [ABSTRACT FROM AUTHOR]

Objective. Recurrence after curative resection for hepatocellular carcinoma (HCC) is a major cause of death from this disease. Factors of primary curative resection are available and potential in the prognosis of follow-up treatment. Our aim was to assess the prognostic significance of primary curative resection factors in recurrent HCC patients undergoing radiofrequency ablation therapy (RFA). Methods. In this retrospective study, we assessed 235 patients who underwent limited RFA of HCC recurrences (tumors ≤ 5 cm ; nodules ≤ 3) after primary curative resection. Factors of primary curative resection were collected, and overall survival and recurrence-free survival were evaluated by the Kaplan-Meier method. Univariate and multivariate analyses were used to identify significant prognostic factors. Results. After a median follow-up of 36 months, 54 patients died, and 128 patients had hepatic recurrence. On univariate analyses, patients whose primary tumors were less differentiated (p = 0.032 and p = 0.048) and required less time to recur (p = 0.013 and p = 0.001) after curative resection displayed poorer overall survival and higher recurrence rates following RFA. On multivariate analyses, the pathologic tumor grade (p = 0.026 and p = 0.038) and recurrence-free survival after primary curative resection (p = 0.028 and p < 0.001) emerged as independent risk factors of survival and HCC recurrence. Conclusions. Primary tumor differentiation and time to recurrence after curative resection are viable prognostic factors of overall survival and further recurrence risk in patients undergoing RFA of recurrent HCC. [ABSTRACT FROM AUTHOR]

Albumin-to-alkaline phosphatase ratio (AAPR), a newly developed blood biomarker, has been reported to have prognostic value in several types of cancer. This study aimed to investigate the predictive value of AAPR in patients with early-stage hepatocellular carcinoma (HCC) undergoing radiofrequency ablation (RFA) as initial therapy. This retrospective study analyzed 445 patients with newly diagnosed HCC undergoing RFA as initial therapy. A series of survival analyses were performed to evaluate the prognostic value of AAPR. Univariate and multivariate analyses were performed to identify independent prognostic factors. An AAPR-based nomogram was constructed, and its predictive performance was validated. Patients with a low AAPR had a significantly reduced recurrence-free survival (RFS) and overall survival (OS) compared with those with a high AAPR. AAPR was found to be an independent prognostic indicator and showed superior discrimination efficacy than other liver function indices. The AAPR-based nomogram had a concordance index value of 0.72 (95% confidence interval [CI]: 0.65–0.79) in the training cohort and 0.72 (95% CI: 0.63–0.81) in the validation cohort, which significantly outperformed other existing staging systems. AAPR serves as a promising indicator of prognosis in patients with early-stage HCC undergoing RFA. The AAPR-based nomogram might contribute to individualized prognosis prediction and clinical decision making. [ABSTRACT FROM AUTHOR]

Background and Aim: Patients with Barcelona Clinic Liver Cancer stage B hepatocellular carcinoma are a heterogeneous population, and the classifications available could not predict the prognosis accurately. Herein, we proposed a new substage classification method, Scoring Method for Intermediate Stage, for precise classification and clinical guidance in hepatocellular carcinoma patients within Barcelona Clinic Liver Cancer stage B. Methods: A total of 1026 stage B patients of hepatocellular carcinoma who underwent transcatheter arterial chemoembolization as a first‐line treatment in Liver Cancer Institute, Zhongshan Hospital, Fudan University were retrospectively enrolled. The prognostic evaluation ability of the new substage classification criteria was analyzed, in comparison with the existing substage classification criteria. Results: Using Scoring Method for Intermediate Stage, 1026 stage B patients were subclassified into three subgroups, based on Child–Pugh score and up‐to‐7 grade, as B1 (scoring 2), B2 (scoring 3 or 4), and B3 (scoring 5 or 6). The median survival time of the three substages was 29 (95% confidence interval [CI]: 25–36), 19 (95% CI: 16–21), and 10 (95% CI: 8–12) months, respectively. More favorable discrimination efficacy was identified by the new criteria in comparison with the existing substage classification criteria, including Bolondi, Kinki, MICAN, and Kim's criteria. Moreover, multivariate analyses indicated that the novel classification was highly associated with prognosis (Hazard ratio(s) = 1.63, 95% CI: 1.43–1.86, P < 0.001). Conclusions: Scoring Method for Intermediate Stage demonstrates satisfying capacity in classifying patients with stage B hepatocellular carcinoma and predicting prognosis. [ABSTRACT FROM AUTHOR]

Objectives. Hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) remains a challenge in management. Transarterial chemoembolization (TACE) has been used for patients with PVTT but efficiency was limited with a median overall survival of 4 to 6.1 months. The aim of this study is to evaluate the efficiency of TACE combined with sorafenib in HBV background HCC with PVTT. Methods. A total of 498 patients were enrolled in the study including 69 patients who received TACE combined with sorafenib and 429 patients treated with TACE alone between January 1st, 2008, and April 30st, 2014. Using the 1:2 propensity score matching, 138 well-balanced patients were enrolled. Overall survival (OS) was compared between the two groups. The Kaplan-Meier method was used to evaluate the OS, and the differences between groups were analyzed with a log-rank test. Results. TACE combined with sorafenib improved the OS of the patients compared with TACE alone (13.0 vs 6.0 months, p<0.001). After propensity score matching, the median OS of combination therapy and TACE were 13.0 and 7.0 months, respectively (p=0.001). Subgroup analysis revealed that the patients younger than 60 years old, male patients, AFP more than 400ng/ml, tumor size more than 5cm, or type III/IV PVTT had OS benefits from TACE combined with sorafenib. Conclusions. Compared with TACE therapy alone, TACE combined with sorafenib could improve OS in HBV background HCC patients with PVTT. The patients who are younger, male, or with more tumor burden may benefit more from combination therapy. [ABSTRACT FROM AUTHOR]

The RIG-I-like RNA helicase (RLR)-mediated interferon (IFN) response plays a pivotal role in the hepatic antiviral immunity. The hepatitis A virus (HAV) and the hepatitis C virus (HCV) counter this response by encoding a viral protease that cleaves the mitochondria antiviral signaling protein (MAVS), a common signaling adaptor for RLRs. However, a third hepatotropic RNA virus, the hepatitis E virus (HEV), does not appear to encode a functional protease yet persists in infected cells. We investigated HEV-induced IFN responses in human hepatoma cells and primary human hepatocytes. HEV infection resulted in persistent virus replication despite poor spread. This was companied by a type III IFN response that upregulated multiple IFN-stimulated genes (ISGs), but type I IFNs were barely detected. Blocking type III IFN production or signaling resulted in reduced ISG expression and enhanced HEV replication. Unlike HAV and HCV, HEV did not cleave MAVS; MAVS protein size, mitochondrial localization, and function remained unaltered in HEV-replicating cells. Depletion of MAVS or MDA5, and to a less extent RIG-I, also diminished IFN production and increased HEV replication. Furthermore, persistent activation of the JAK/STAT signaling rendered infected cells refractory to exogenous IFN treatment, and depletion of MAVS or the receptor for type III IFNs restored the IFN responsiveness. Collectively, these results indicate that unlike other hepatotropic RNA viruses, HEV does not target MAVS and its persistence is associated with continuous production of type III IFNs. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the most prevalent and malignant type of liver cancer. Besides the high incidence, the resistance to chemotherapy is a major problem that leads to the high mortality of HCC. Recently, aberrant expression of long noncoding RNAs (lncRNAs) has been considered as a primary feature of many types of cancer. However, the genome-wide expression pattern and associated functional implications of lncRNAs in chemo-resistant HCC cells remain unknown. In this study, we identified 120 differentially expressed lncRNAs with 61 up-regulated and 59 down-regulated (fold change > 2, p < 0.05) along with 421 differentially expressed mRNAs with 228 up-regulated and 193 down-regulated (fold change > 2, p < 0.05) in oxaliplatin-resistant (MHCC97H-OXA) HCC cells, compared to parental oxaliplatin-sensitive (MHCC97H) by microarray. The underlying pathways were related to cell death, proliferation, cellular response to stimulus, including p53 pathway, ErbB pathway and MAPK pathway. Further, 16 lncRNAs were selected for validation of microarray results with quantitative PCR, and a strong correlation was identified between the qPCR results and microarray data. We demonstrated for the first time that ENST00000438347, NR_073453 and ENST00000502804 were up-regulated in MHCC97H-OXA cells as well as chemo-resistant HCC cancerous tissues. Moreover, the expression of ENST00000518376 was significantly associated with the tumor size and differentiation. Overall survival analysis showed that high expression of ENST00000438347 and ENST00000518376 was associated with poor prognosis in HCC patients. Taken together, our results reveal that the expression profile in oxaliplatin-resistant HCC is significantly altered including lncRNAs. And a series of de novo lncRNAs play important functions in HCC oxaliplatin resistance and HCC progression. [ABSTRACT FROM AUTHOR]

Aim: Pilot studies have evaluated the correlation between hypoxia-inducible factor-1α (HIF-1α) overexpression and clinical outcome in hepatocellular carcinoma (HCC) patients. However, the results remain inconclusive. To comprehensively and quantitatively summarize the evidence on the suitability of HIF-1α to predict the prognosis of patients with HCC, a meta-analysis was carried out. Methods: Systematic literature searches were applied to PubMed, Elsevier and Web of Science databases until Feb. 2013. Seven studies (953 patients) were included in this meta-analysis. Pooled measure was calculated from the available data to evaluate the association between tissue -based HIF-1α level and overall survival (OS) and disease-free survival (DFS) in HCC patients. The relation between HIF-1α expression and vascular invasion was also assessed. Data were synthesized with fixed or random effect model, hazard ration (HR) or odds ratio (OR) with its 95% confidence interval (CI) was used as the effect size estimate. Result: The combined data suggested that HIF-1α overexpression in HCC correlated with poor OS [HR = 1.65 (95% (CI): 1.38, 1.97)] and DFS [HR = 2.14 (95% CI: 1.39, 3.29)]. And high HIF-1α expression tended to be associated with vascular invasion [OR = 2.21 (95% CI: 1.06, 4.57)]. Conclusion: HIF-1α overexpression indicates a poor prognosis for patients with HCC, it may also have predictive potential for HCC invasion and metastasis. [ABSTRACT FROM AUTHOR]

Background: Although transarterial chemoembolization (TACE) has been used extensively for advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT), no consensus has been reached and an evidence base for practice is lacking. This meta-analysis evaluated the efficacy and safety of TACE for treatment of HCC with PVTT.Methods: Ovid Medline, EMBASE, Web of Knowledge, and Cochrane library databases were searched up to August 2012 for controlled trials assessing TACE in patients with PVTT. Data concerning the study design, characteristics of trials, and outcomes were extracted. Hazard ratio (HR) and 95% confidence interval (CI) were calculated using random effects models.Results: Eight controlled trials involving 1601 HCC patients were included. TACE significantly improved the 6-month (HR, 0.41; 95% CI: 0.32-0.53; z, 6.28; p = 0.000) and 1-year (HR, 0.44; 95% CI: 0.34-0.57; z, 6.22; p = 0.000) overall survival of patients with PVTT compared with conservative treatment. Subgroup analyses showed that TACE was significantly effective in HCC patients whether with main portal vein (MPV) obstruction or with segmental PVTT. Fatal complications were rare, even in patients with MPV obstruction. Temporary liver decompensation and postembolization syndrome occurred frequently. However, they could be treated successfully with conservative treatment.Conclusions: TACE, as a safe treatment, has potential for incurring a survival benefit for advanced HCC with PVTT, even with MPV obstruction. Further large randomized controlled trials may be needed to confirm this result. [ABSTRACT FROM AUTHOR]

Background and purpose: Hepatocellular carcinoma (HCC) is still one of the most prevalent malignancies in China and throughout the world, while most of these patients are in intermediate or advanced stage when diagnosed. The resistance of advanced HCC to chemotherapy or interventional therapy is one of the crucial factors significantly limiting the survival and prognosis of patients. However, the molecular mechanisms involved have not been fully clarified. We previously found that the long non-coding RNA LINC00601 was highly expressed in oxaliplatin resistant HCC cells. This study aimed to explore the role and specific mechanism of LINC00601 in regulating the sensitivity of HCC cells to oxaliplatin chemotherapy, to provide a novel target to identify proper candidates for oxaliplatin chemotherapy, and the theoretical basis for the treatment of patients with advanced HCC. Methods: Human HCC cell line MHCC-97H and Hep-3B were induced to establish oxaliplatin resistant cell lines 97H-OXR and 3B-OXR by long-term low-dose oxaliplatin treatment in vitro. Real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR) was used to detect the expression of LINC00601 in cell lines. Cell counting kit-8 (CCK-8) assay was performed to detect the effect of LINC00601 gene silencing or overexpression on the sensitivity of HCC cells to oxaliplatin treatment. Flow cytometry and Western blot experiments were conducted to detect the alteration of cell apoptosis. Finally, Western blot and immunofluorescence staining were applied to explore the nuclear translocation of growth arrest and DNA damage-inducible protein 45α (GADD45A), and RNA pull-down together with RNA immunoprecipitation (RIP) experiments were carried out to validate the combination of LINC00601 and GADD45A. Results: Compared with the control cells, LINC00601 expression level was significantly increased in oxaliplatin resistant cells. Both induced-oxaliplatin-resistant cells and LINC00601-overexpressed MHCC-97H cells were observed to be less sensitive to oxaliplatin administration. On the contrary, the down-regulation of LINC00601 expression in oxaliplatin resistant cells significantly increased the sensitivity to oxaliplatin treatment. Meanwhile, upregulated expression of LINC00601 inhibited the apoptosis level of HCC cell lines after oxaliplatin treatment, which was consistent with the sensitivity levels of different cell lines to oxaliplatin as above. In addition, the overexpression of LINC00601 reduced the nuclear translocation of GADD45A and the expression of GADD45A in the nucleus. Furthermore, the combination of LINC00601 and GADD45A was observed. Conclusion: LINC00601 might regulate the apoptotic progress of cells after oxaliplatin chemotherapy by interfering with the nuclear translocation of GADD45A, which eventually lead to the resistance to oxaliplatin.

Growth arrest-specific gene 7 (Gas7) was involved in various cellular functions, although its specific roles and molecular mechanisms in hepatocellular carcinoma (HCC) remained unclear. So the current study was to investigate the role of Gas7 in HCC. Our findings revealed that Gas7 was downregulated in various HCC cell lines and low Gas7 expression was associated with decreased overall survival in patients with HCC. Additionally, our functional assays showed that Gas7 inhibited cell proliferation and migration, induced cell cycle arrest, apoptosis, and autophagy, and enhanced oxaliplatin sensitivity by inhibiting the PI3K/Akt signaling pathway. We also observed that transcription factor Sp1 was responsible for inhibiting Gas7. These findings provide insights into the role and elucidated a potential mechanism of Gas7 in HCC progression and metastasis. It was also observed that the Sp1/Gas7/PI3K/Akt axis was critical for malignant phenotype and oxaliplatin sensitivity in HCC. Therefore, Gas7 can be considered as a prognostic predictor and therapeutic target for HCC. • Low Gas7 expression was associated with decreased overall survival in patients with HCC. • Gas7 inhibited malignant phenotype of HCC cells by inhibiting the PI3K/Akt signaling pathway. • Transcription factor Sp1 was responsible for inhibiting Gas7 in HCC. • Gas7 can be considered as a prognostic predictor and therapeutic target for HCC. [ABSTRACT FROM AUTHOR]