Disease-free Survival In Hepatocellular Carcinoma Patients Research Articles

Prognostic impact of CD68+ tumor-associated macrophages in hepatocellular carcinoma: A meta-analysis.

Evidence from clinical research suggests that the tumor-associated macrophages (TAMs) were associated with prognosis in hepatocellular carcinoma (HCC). The aim of the present meta-analysis was to conduct a qualitative analysis to explore the prognostic value of CD68 + TAMs in HCC. This study conducted a systematic search in Pubmed, Embase, the Cochrane Library and China National Knowledge Internet from inception of the databases to November 2023. The hazard ratio (HR) and 95% confidence interval (CI) were calculated employing fixed-effect or random-effect models depending on the heterogeneity of the included trials. The Newcastle-Ottawa Scale was used to evaluate the risk of prejudice. We analyzed 4362 HCC patients. The present research indicated that the expression levels Of CD68 + TAMs were significantly associated with overall survival (OS) (HR = 1.55, 95% CI: 1.30-1.84) and disease-free survival (DFS) (HR = 1.44, 95% CI: 1.17-1.78). Subgroup analysis based on cutoff values showed that the "Median" subgroup showed a pooled HR of 1.66 with a 95% CI ranging from 1.32 to 2.08, which was slightly higher than the "Others" subgroup that exhibited a pooled HR of 1.40 and a 95% CI of 1.07 to 1.84. The "PT" subgroup had the highest pooled HR of 1.68 (95% CI: 1.19-2.37), indicating a worse OS compared to the "IT" (pooled HR: 1.50, 95% CI: 1.13-2.01) and "Mix" (pooled HR: 1.52, 95% CI: 1.03-2.26) subgroups. Moreover, in the sample size-based analysis, studies with more than 100 samples (>100) exhibited a higher pooled HR of 1.57 (95% CI: 1.28 to 1.93) compared to studies with fewer than 100 samples (<100), which had a pooled HR of 1.45 (95% CI: 1.00-2.10). The analysis suggests that CD68 + TAMs were significantly associated with unfavorable OS and DFS in HCC patients, and may be served as a promising prognostic biomarker in HCC. However, more large-scale trials are needed to study the clinical value of TAMs in HCC.

TRIM29 modulates proteins involved in PTEN/AKT/mTOR and JAK2/STAT3 signaling pathway and suppresses the progression of hepatocellular carcinoma.

Tripartite motif-containing 29 (TRIM29), also known as the ataxia telangiectasia group D-complementing (ATDC) gene, has been reported to play an oncogenic or tumor suppressive role in developing different tumors. So far, its expression and biological functions in hepatocellular carcinoma (HCC) remain unclear. We investigated TRIM29 expression pattern in human HCC samples using quantitative RT-PCR and immunohistochemistry. Relationships between TRIM29 expression level, clinical prognostic indicators, overall survival (OS), and disease-free survival (DFS) were evaluated by Kaplan-Meier analysis and Cox proportional hazards model. A series of in vitro experiments and a xenograft tumor model were conducted to detect the functions of TRIM29 in HCC cells. RNA sequencing, western blotting, and immunochemical staining were performed to assess the molecular regulation of TRIM29 in HCC. We found that the mRNA and protein levels of TRIM29 were significantly reduced in HCC samples, compared with adjacent noncancerous tissues, and were negatively correlated with poor differentiation of HCC tissues. Survival analysis confirmed that lower TRIM29 expression significantly correlated with shorter OS and DFS of HCC patients. TRIM29 overexpression remarkably inhibited cell proliferation, migration, and EMT in HCC cells, whereas knockdown of TRIM29 reversed these effects. Moreover, deactivation of the PTEN/AKT/mTOR and JAK2/STAT3 pathways might be involved in the tumor suppressive role of TRIM29 in HCC. Our findings indicate that TRIM29 in HCC exerts its tumor suppressive effects through inhibition of the PTEN/AKT/mTOR and JAK2/STAT3 signaling pathways and may be used as a potential biomarker for survival in patients with HCC.

Thermal ablation versus liver resection for hepatocellular carcinoma in patients with cirrhosis: a systematic review and meta-analysis of propensity-score matched studies

The outcomes of cirrhotic patients with hepatocellular carcinoma (HCC) after thermal ablation (TA) versus liver resection (LR) are debated. We aimed to compare the overall survival (OS), disease-free survival (DFS), and operative outcomes after TA and LR for HCC in patients with cirrhosis. Until November 15, 2022, we searched PubMed, Embase, and Cochrane databases by using Medical Subject Heading terms and other terms, and used the Newcastle-Ottawa literature evaluation scale to assess the quality of selected studies. OS, DFS, and operative outcomes were extracted and analyzed. The meta-analysis showed that 5 propensity-score matched (PSM) studies including 933 patients (463 TA vs. 470 LR) were included. After analysis, TA and LR had similar results at 1-year OS (odds ratio [OR] 1.68; 95% confidence interval [CI] 1.01–2.78; P = 0.05) and 3-year OS (OR 0.76; 95% CI 0.56–1.04; P = 0.08), whereas LR increased 5-years OS (OR 0.37; 95% CI 0.18–0.74; P = 0.005). In addition to the DFS, the 1-year DFS was significantly higher in patients with LR. However, there were no obvious differences in 3-year and 5-year DFS when comparing TA and LR. The length of operative time and hospital stay were longer in the LR group. Besides, the LR group had significantly higher rate of perioperative blood transfusions and major complications. Our research proved that LR took advantage of OS and DFS for HCC patients with cirrhosis. Additional well-designed randomized controlled trials are needed.

Transferrin receptor 1 promotes hepatocellular carcinoma progression and metastasis by activating the mTOR signaling pathway.

Aberrant iron metabolism is commonly observed in multiple tumor types, including hepatocellular carcinoma (HCC). However, as the key regulator of iron metabolism involved in iron absorption, the role of transferrin receptor (TFRC) in HCC remains elusive. The mRNA and protein expression of TFRC were evaluated in paired HCC and adjacent non-tumor specimens. The correlation between TFRC level and clinicopathological features or prognostic significance was also analyzed. The role of TFRC on biological functions was finally studied in vitro and in vivo. The TFRC level was remarkably upregulated in HCC tissues compared to paired peritumor tissues. Overexpressed TFRC positively correlated with serum alpha-fetoprotein, carcinoembryonic antigen, and poor tumor differentiation. Multivariate analysis demonstrated that upregulated TFRC was an independent predictive marker for poorer overall survival and disease-free survival in HCC patients. Loss of TFRC markedly impaired cell proliferation and migration in vitro and notably suppressed HCC growth and metastasis in vivo, while overexpression of TFRC performed an opposite effect. Mechanistically, the mTOR signaling pathway was downregulated with TFRC knockdown, and the mTOR agonist MHY1485 completely reversed the biological inhibition in HCC cells caused by TFRC knockdown. Furthermore, exogenous ferric citrate (FAC) or iron chelator reversed the changed biological functions and signaling pathway expression of HCC cells caused by TFRC knockdown or overexpression, respectively. Our study indicates that TFRC exerts an oncogenic role in HCC and may become a promising therapeutic target to restrain HCC progression.

Development and validation of metabolic models for predicting survival and immune status of hepatocellular carcinoma patients.

Metabolic reprogramming is associated with the carcinogenesis of hepatocellular carcinoma (HCC). The effects of metabolism-related genes on predicting survival and immune status in HCC remain unclear. To develop and validate metabolic models for predicting the survival and immune status of HCC patients. The metabolic core genes for overall survival (OS) and disease-free survival (DFS) were retrieved. Then, glycolysis and fatty acid metabolism prognostic models were constructed and validated using The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) data. Decision trees based on machine learning were developed for classifying the prognostic risks of HCC patients. The associations between the metabolic signatures, immunotherapy and immune cell infiltration were investigated. Experimental validations were performed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). We identified 30 prognostic core genes for glycolysis metabolism and 12 prognostic core genes for fatty acid metabolism. Subsequently, 2 glycolysis models and 2 fatty acid metabolism models were developed to predict the OS and DFS of HCC patients, respectively. Two decision trees were constructed to classify the low-, intermediateand high-risk groups of HCC patients for OS and DFS. Moreover, the patients in the high-risk groups of glycolysis and fatty acid metabolic models tended to have higher expression of programmed cell death ligand-1 (PD-L1 or CD274), programmed cell death 1 (PDCD1), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), and lymphocyte activating 3 (LAG3). Most of the metabolic core genes were significantly associated with immune cell infiltration. In addition, ATP-binding cassette subfamily B member 6 (ABCB6), peptidylprolyl isomerase A (PPIA), uroporphyrinogen decarboxylase (UROD), and non-SMC condensin II complex subunit H2 (NCAPH2) were positively correlated with both tumor mutational burden (TMB) and microsatellite instability (MSI) scores. The expression of ABCB6, PPIA, UROD, and NCAPH2 was validated using RT-qPCR and IHC. We established novel prognostic models based on metabolism-related genes to better predict the outcome and immune status of HCC patients.

The upregulation of CLGN in hepatocellular carcinoma is potentially regulated by hsa-miR-194-3p and associated with patient progression.

Patients with hepatocellular carcinoma (HCC) have poor prognosis, especially in advanced stages. Targeted therapy is the main treatment for advanced HCC patients, but the optimal targets for HCC remain poorly understood. The main purpose of this study was to identify potential novel prognostic markers and therapeutic targets. Firstly, differentially expressed genes (DEGs) in HCC were identified from the Gene Expression Omnibus (GEO) database. The expression, significance in prognosis, and potential mechanisms of DEGs were analyzed using GEPIA, TIMER, HPA, Kaplan Meier Plotter, CBioPortal, miRWalk, TargetScan, and ENCORI databases. Immunohistochemical staining was used to determine the protein expression levels of potential candidate genes. The mRNA levels of MND1, STXBP6, and CLGN were significantly increased in HCC (p< 0.01). HCC patients with elevated CLGN mRNA levels had poorer overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and disease-specific survival (DSS) (p < 0.05). Higher MND1 mRNA levels significantly correlated with poorer DFS in HCC patients (p< 0.05). However, there was no significant correlation between STXBP6 expression and prognosis of HCC (p> 0.05). Further analysis revealed that patients with elevated CLGN mRNA expression in advanced pathology stages had poorer prognosis (p< 0.01). In addition, CLGN protein levels were elevated in HCC compared to their levels in normal tissues. The mRNA levels of CLGN had no significant correlation with the abundance of six common tumor infiltrating lymphocytes in HCC (COR < 0.5). Moreover, the mutation rate of CLGN was less than 1% in HCC patients (10/1089). Finally, the expression level of hsa-miR-194-3p in HCC was significantly lower than that in normal tissues (p < 0.05), and prognosis of HCC with low expression of hsa-miR-194 was poor (p < 0.05). The upregulation of CLGN in HCC is significantly associated with poor patient prognosis, especially in the advanced stages, and may be regulated by hsa-miR-194-3p. These findings suggest that CLGN may be closely related to the progression of HCC, and is a potential therapeutic target and prognostic indicator for patients with advanced HCC.

Prognostic factors for disease-free survival in postoperative patients with hepatocellular carcinoma and construction of a nomogram model.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and has a high risk of invasion and metastasis along with a poor prognosis. To investigate the independent predictive markers for disease-free survival (DFS) in patients with HCC and establish a trustworthy nomogram. In this study, 445 patients who were hospitalized in The First Affiliated Hospital of Anhui Medical College between December 2009 and December 2014 were retrospectively examined. The survival curve was plotted using the Kaplan-Meier method and survival was determined using the log-rank test. To identify the prognostic variables, multivariate Cox regression analyses were carried out. To predict the DFS in patients with HCC, a nomogram was created. C-indices and receiver operator characteristic curves were used to evaluate the nomogram's performance. Decision curve analysis (DCA) was used to evaluate the clinical application value of the nomogram. Longer DFS was observed in patients with the following characteristics: elderly, I-II stage, and no history of hepatitis B. The calibration curve showed that this nomogram was reliable and had a higher area under the curve value than the tumor node metastasis (TNM) stage. Moreover, the DCA curve revealed that the nomogram had good clinical applicability in predicting 3- and 5-year DFS in HCC patients after surgery. Age, TNM stage, and history of hepatitis B infection were independent factors for DFS in HCC patients, and a novel nomogram for DFS of HCC patients was created and validated.

Integrated Bioinformatic Investigation of EXOSCs in Hepatocellular Carcinoma Followed by the Preliminary Validation of EXOSC5 in Cell Proliferation.

The Exosome complex (EXOSC) is a multiprotein complex that was originally discovered as the machinery of RNA degradation. Interestingly, recent studies have reported that EXOSC family members (EXOSCs) are associated with various human diseases, including cancers. It will be interesting to investigate whether EXOSCs are related to the processes of hepatocellular carcinoma (HCC). In this study, multiple public databases and experimental validation were utilized to systemically investigate the role of EXOSCs, especially EXOSC5, in HCC. It is worth considering that the mRNA and protein levels of many EXOSCs were elevated in HCC, although there were some differences in the results from different database analyses. The over-expression of EXOSCs could predict HCC to some extent, as evidenced by the positive correlation between the elevated EXOSCs and alpha fetoprotein (AFP) levels, as well as with a high accuracy, as shown by the receiver operating characteristic curve analysis. Additionally, higher mRNA expressions of specific EXOSCs were significantly related to clinical cancer stage, shorter overall survival and disease-free survival in HCC patients. A moderate mutation rate of EXOSCs was also observed in HCC. Furthermore, a gene functional enrichment analysis indicated that EXOSCs were mainly involved in the metabolism of RNA. Moreover, we revealed that the expression of EXOSCs is remarkably related to immune cell infiltration. Finally, EXOSC5 was upregulated in HCC tissues and cell lines, promoting cell growth and proliferation via activated signal transducer and activator of transcription 3 (STAT3). The bioinformatic analyses, following verification in situ and in vitro, provided a direction for further functions and underlying mechanism of EXOSCs in HCC.

MiR-3154 promotes hepatocellular carcinoma progression via suppressing HNF4α.

MicroRNAs (miRNAs) play an important role in cancer proliferation, metastasis, drug resistance and apoptosis by targeting oncogenes or tumor suppressor genes. miR-3154 has been reported to be up-regulated in cervical cancer and leukemia, but its role in hepatocellular carcinoma (HCC) remains unclear. Here, we for the first time demonstrated that miR-3154 was elevated in HCC and liver cancer stem cells (CSCs). Up-regulated miR-3154 was associated with overall survival and disease-free survival of HCC patients. MiR-3154 knockdown inhibits HCC cells self-renewal, proliferation, metastasis, and tumorigenesis. Mechanistically, miR-3154 target directly to HNF4α. MiR-3154 knockdown upregulated HNF4α mRNA and protein expression. HNF4α interference abolish the differences of self-renewal, proliferation, metastasis, and tumorigenesis between miR-3154 knockdown cells and control hepatoma cells. Furthermore, miR-3154 expression was negatively correlated with HNF4α in HCC tissues. The combined HHC panels exhibited a better disease-free survival prognostic value for HCC patients than any of these components alone. More importantly, miR-3154 determines the responses of hepatoma cells to lenvatinib treatment. Analysis of patient cohort and patient-derived xenografts (PDXs) further suggest that miR-3154 might predict lenvatinib clinical benefit in HCC patients. In conclusion, we reveal the crucial role of miR-3514 in HCC progression and lenvatinib response, suggesting potential therapeutic targets for HCC.

The role of tumor-infiltrating B cells in the tumor microenvironment of hepatocellular carcinoma and its prognostic value: a bioinformatics analysis.

BackgroundAccumulating evidence indicates that tumor heterogeneity is characterized by distinct immunosubtypes. However, prior studies have mainly focused on the functions of T cells. The role of tumor-infiltrating B cells in the microenvironment of hepatocellular carcinoma (HCC) requires further investigation.MethodsWe conducted an integrative analysis of single cell RNA sequencing (scRNA-seq) datasets in HCC tumor samples from Gene Expression Omnibus database. We analyzed the features of B cells in normal liver tissue and HCC. Additionally, we conducted a deconvolution analysis using the matrix of scRNA-seq datasets and the RNA-seq datasets in The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) database. The survival analyses of the TCGA-LIHC cohort with different B cell infiltration rates and was further validated. Finally, we performed immunohistochemistry analysis of primary tumor tissue of HCC patients using antibodies against CD79A and validated the impact of tumor-infiltrating B cells in the prognosis of LIHC.ResultsWe identified several subtypes of B cells in the microenvironment of HCC, including the plasma cells and naïve B cells. The relative ratio of B cells, but not the plasma cells, was significantly decreased in HCC as compared to the normal liver tissue (P<0.05). In addition, genes related to antigen presentation and cell proliferation were decreased in tumor-infiltrating B cells (P<0.05). The observation of B cell infiltration was further validated with the TCGA-LIHC cohort. The overall survival and disease-free survival in HCC patients with higher B-cell infiltration rate were significantly longer than those in the lower infiltration group (P<0.05) in the TCGA-LIHC cohort. Moreover, we demonstrated higher infiltration rates of B cells were significantly associated with a better prognosis of HCC in our cohort.ConclusionsTumor-infiltrating B cells potentially exert a tumor-suppressive function in the microenvironment of HCC and the higher levels of B cell infiltration are associated with a favorable outcome of HCC. Targeted activation of B cells may improve the tumor immune-targeted therapy.

A novel combined prognostic nutritional index and aspartate aminotransferase-to-platelet ratio index-based score can predict the survival of patients with hepatocellular carcinoma who undergo hepatic resection.

Inflammation-, nutrition-, and liver fibrosis-related markers are recognized as prognostic for hepatocellular carcinoma (HCC) patients. This study, therefore, assessed the preoperative prognostic utility of the combination of these markers in patients with HCC. This single-center retrospective study included patients who underwent hepatic resection for HCC between 2004 and 2017. A total of 454 patients were divided into training (n = 334) and validation (n = 120) cohorts by random sampling. The predictive impact on surgical outcomes was evaluated using receiver operating characteristic (ROC) curves of these prognostic values in the training cohort. The prognostic nutritional index (PNI) and aspartate aminotransferase-to-platelet ratio index (APRI) were the strongest diagnostic values (areas under the ROC curves: 0.627 and 0.646, respectively). A scoring system (over 0-2 points) was developed using optimal cutoff values (for PNI < 46.5 scored as 1 point; for APRI > 0.98 scored as 1 point). An increased PNI-APRI score was an independent prognostic factor for both the overall and disease-free survival in HCC patients. Finally, the clinical feasibility of the PNI-APRI score was confirmed in the validation cohort. The PNI-APRI score is a useful marker for predicting surgical outcomes of HCC patients.

Alpha-Fetoprotein Ratio Predicts Alpha-Fetoprotein Positive Hepatocellular Cancer Patient Prognosis after Hepatectomy.

Background This study was conducted to investigate the effect of alpha-fetoprotein (AFP) ratio on the prognosis of AFP-positive hepatocellular carcinoma (HCC) patients after hepatectomy. Methods We retrospectively included 879 HCC patients with AFP-positive who underwent hepatectomy from February 2012 to October 2017 and randomly divided into training cohort and validation cohort. AFP ratio was equal to the AFP level within one week before hepatectomy to AFP level within 20-40 days after surgery. The end point of follow-up was disease-free survival (DFS) and overall survival (OS). Results AFP ratio was not associated with clinical characteristics in training cohort and validation cohort. According to the X-tile software, the optimum cut-off point was 17.8 for AFP ratio. Significant differences between AFP ratio high and AFP ratio low were observed in DFS and OS in both cohort (p < 0.05). Kaplan-Meier curves and receiver-operating curves were showed that AFP ratio was better than AFP level preoperation in predicting the prognosis of AFP-positive HCC patients after hepatectomy. The multivariate analysis demonstrated that AFP ratio was a significant independent risk factor for both OS and DFS in HCC patients with AFP-positive. Conclusions AFP ratio might be a prognosis predictor for HCC patients with AFP-positive after hepatectomy.

The Clinicopathologic and Prognostic Significance of c-Myc Expression in Hepatocellular Carcinoma: A Meta-Analysis.

Background: The incidence and mortality rates of hepatocellular carcinoma (HCC) are increasing worldwide. Therefore, there is an urgent need to elucidate the molecular drivers of HCC for potential early diagnosis and individualized treatment. Whether c-Myc expression plays a role in the clinicopathology and prognosis of patients with HCC remains controversial. This meta-analysis aimed to survey the prognostic role of c-Myc in HCC. Methods: We searched PubMed, Cochrane Library, Embase, Web of Science, and Google Scholar databases for studies published through March 2020 that examined the association between c-Myc expression and clinicopathology or prognosis in HCC patients. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were used to investigate the prognostic significance of c-Myc expression. Odds ratios were calculated to evaluate the association between c-Myc expression and clinicopathologic features. We also tested for publication bias. Results: Our meta-analysis included nine studies with 981 patients with HCC published between 1999 and 2016. A meta-analysis of these studies demonstrated that high c-Myc expression indicated a poor overall survival (OS) (HR = 2.260, 95% CI: 1.660–3.080, and p < 0.001) and disease-free survival (DFS) (HR = 1.770, 95% CI: 1.430–2.450, and p < 0.001) in patients with HCC. However, high c-Myc expression was not associated with HBsAg, pathological type, TNM stage, or cirrhosis. We did not find any significant publication bias among the included studies, indicating that our estimates were robust and reliable. Conclusion: c-Myc overexpression could predict poor OS and DFS in HCC patients. c-Myc could be a useful prognostic biomarker and therapeutic target for HCC.

Upregulation of Nei-Like DNA Glycosylase 3 Predicts Poor Prognosis in Hepatocellular Carcinoma.

Background Accumulating evidence has suggested that Nei-like DNA glycosylase 3 (NEIL3) is associated with human tumors. However, there are few studies on the role of NEIL3 in hepatocellular carcinoma (HCC). The aim of this study was to investigate the expression profile of NEIL3 and its clinical relevance in HCC. Materials and Methods A total of 130 HCC and corresponding nontumor tissues were collected to perform immunohistochemistry (IHC). The clinical relevance and prognostic value of NEIL3 in HCC were analyzed by the chi-square test, Kaplan–Meier analysis, the Cox proportional hazard model, and nomogram. Results IHC showed that the NEIL3 protein level was remarkably upregulated in tumor tissues compared with nontumor tissues (fold change = 1.24; P < 0.001). High NEIL3 expression was significantly correlated with BCLC stage (P=0.004) and TNM stage (P=0.005). Overall survival (OS) and disease-free survival (DFS) rates in the high NEIL3 expression group were significantly worse than those in the low NEIL3 expression group (P=0.007 and P=0.004, respectively). Furthermore, subgroup analysis showed that high NEIL3 expression predicted worse OS and DFS for HCC patients with advanced TNM stage, poorly differentiated tumor, HBsAg positive, or cirrhosis. Multivariate analysis and the prognostic nomograms revealed that tumor NEIL3 level may serve as a promising prognostic indicator for OS and DFS in HCC patients. Conclusion Our findings suggested that NEIL3 might be a potential prognosis assessment marker and therapeutic target for HCC patients.

Impact of Postoperative Complications on Long-Term Survival After Resection of Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.

Controversy exists over the relationship between postoperative complications (POCs) and long-term survival for hepatocellular carcinoma (HCC) after hepatectomy. This study aimed to evaluate the impact of POCs on overall survival (OS) and disease-free survival (DFS) for HCC after liver resection. The PubMed, EMBASE, and Cochrane Library databases were used to search for eligible studies published through 18 April 2020, and studies comparing the long-term outcomes between HCC patients with and without POCs after hepatectomy were included. A random-effects model was used to calculate the pooled hazard ratio (HR) with a 95% confidence interval (CI). Subgroup analysis and meta-regression were performed to assess the potential influence of study-, patient-, and tumor-related factors on the relationship between POCs and oncologic outcomes and to adjust their effect. This study was registered at the International Prospective Register of Systematic Reviews (CRD42019136109). Thirty-seven studies, including 14,096 patients, were deemed eligible and included in this study. Compared with those without POCs, patients who developed POCs had a significant reduction in OS (HR 1.39, 95% CI 1.28-1.50, P < 0.001; prediction interval 1.04-1.85) and tended to have worse DFS (HR 1.25, 95% CI 1.16-1.35, P < 0.001; prediction interval 0.98-1.60). Contour-enhanced funnel plots suggested a risk of publication bias. Subgroup analysis and meta-regression showed that POCs remained a threat to OS and DFS regardless of the influence of clinicopathological factors. This study demonstrated that POCs had an adverse impact on OS and DFS in HCC patients after liver resection.

NAD(P)HX epimerase downregulation promotes tumor progression through ROS/HIF-1α signaling in hepatocellular carcinoma.

Reactive oxygen species (ROS) derived from aberrant tumor metabolism could contribute to tumor invasion and metastasis. NAD(P)HX Epimerase (NAXE), an epimerase that allows the repair of damaged forms of antioxidant NADPH, is a potential cellular ROS scavenger and its role in tumor development is still elusive. Here, we found that NAXE is significantly downregulated in hepatocellular carcinoma (HCC) tissues and cell lines. NAXE downregulation is associated with poor clinicopathological characteristics and is an independent risk factor for overall and disease‐free survival of HCC patients after liver resection. In addition, low NAXE expression could identify worse prognosis of HCC patients before vascular invasion or in early stages of disease. In particularly, low NAXE expression in HCC is markedly associated with microvascular invasion (MVI) and its combination with MVI predicts poorer prognosis of HCC patients after liver resection. Furthermore, in vitro and in vivo experiments both showed that knockdown of NAXE expression in HCC cells promoted migration, invasion, and metastasis by inducing epithelial‐mesenchymal transition (EMT), whereas NAXE overexpression causes the opposite effects. Mechanistically, low NAXE expression reduced NADPH levels and further caused ROS level increase and hypoxia‐inducible factor‐1α (HIF‐1α) activation, thereby promoting invasion and metastasis of HCC by facilitating EMT. What is more, the tumor‐promoting effect of NAXE knockdown in HCC xenograft can be abolished by giving mice N‐acetyl‐l‐cysteine (NAC) in drinking water. Taken together, our findings uncovered a tumor suppressor role for NAXE in HCC by scavenging excessive ROS and inhibiting tumor‐promoting signaling pathways, suggesting a new strategy for HCC therapy by targeting redox signaling.

Effectiveness of Anatomical Resection for Small Hepatocellular Carcinoma: a Propensity Score–Matched Analysis of a Multi-institutional Database

BackgroundThe superiority of outcomes associated with anatomical resection (AR) versus those associated with non-anatomical resection (NAR) remains controversial in patients with hepatocellular carcinoma (HCC). The aim of this study was to evaluate the significance of AR on therapeutic outcomes of patients with small HCCs (≤ 5 cm), using propensity score–matched (PSM) analysis. MethodsA total of 195 patients who had undergone elective hepatic resection for small HCCs (≤ 5 cm) were included in this study. We conducted PSM analysis for baseline characteristics (age, sex, hepatitis virus status, retention rate of indocyanine green at 15 min, and Child-Pugh grade), preoperative serum α-fetoprotein, and tumor characteristics (tumor size, tumor number, portal vein invasion, and surgical margin status) to eliminate potential selection bias. The prognostic significance of AR on the disease-free and overall survival was analyzed in patients selected by PSM analysis. ResultsApplying PSM analysis, the patients were divided into PSM-AR (N = 66) and PSM-NAR (N = 66) groups. Disease-free survival was significantly better in the PSM-AR group than that of the PSM-NAR group (P = 0.018), while there was no significant difference in the overall survival between the PSM-AR and PSM-NAR groups (P = 0.292). The univariate HRs of the PSM-AR group were 0.55 (95% CI, 0.33–0.90) for disease-free survival and 0.61 (95% CI, 0.24–1.53) for overall survival, respectively. Remnant liver recurrence was significantly lower in the AR group (P = 0.014). ConclusionsAR may improve the disease-free survival in HCC patients with tumors of ≤5 cm diameter.

Nujiangexanthone A Inhibits Hepatocellular Carcinoma Metastasis via Down Regulation of Cofilin 1.

Hepatocellular carcinoma (HCC) is one of the malignant tumors with poor prognosis. High expression level of cofilin 1 (CFL1) has been found in many types of cancers. However, the role of CFL1 in HCC hasn’t been known clearly. Here, we found that CFL1 was up regulated in human HCC and significantly associated with both overall survival and disease-free survival in HCC patients. Nujiangexanthone A (NJXA), the caged xanthones, isolated from gamboge plants decreased the expression of CFL1, which also inhibited the migration, invasion and metastasis of HCC cells in vitro and in vivo. Down regulation of CFL1 inhibited aggressiveness of HCC cells, which mimicked the effect of NJXA. Mechanism study indicated that, knockdown of CFL1 or treatment with NJXA increased the level of F-actin and disturbed the balance between F-actin and G-actin. In conclusion, our findings reveal the role of CFL1 in HCC metastasis through the CFL1/F-actin axis, and suggest that CFL1 may be a potential prognostic marker and a new therapeutic target. NJXA can effectively inhibit the metastasis of HCC cells by down regulating the expression of CFL1, which indicates the potential of NJXA for preventing metastasis in HCC.

PSMC2 Regulates Cell Cycle Progression Through the p21/Cyclin D1 Pathway and Predicts a Poor Prognosis in Human Hepatocellular Carcinoma.

Proteasome 26S subunit ATPase 2 (PSMC2) plays a pathogenic role in various cancers. However, its function and molecular mechanism in hepatocellular carcinoma (HCC) remain unknown. In this study, tissue microarray (TMA) analysis showed that PSMC2 is highly expressed in HCC tumors and correlates with poor overall and disease-free survival in HCC patients. Multivariate Cox regression analysis revealed that PSMC2 is an independent prognostic factor for HCC patients. Furthermore, our results showed that PSMC2 knockdown inhibited cell proliferation and suppressed tumorigenesis in vivo. Knockdown of PSMC2 increased the expression of p21 and therefore decreased the expression of cyclin D1. Dual-luciferase reporter assays indicated that depletion of PSMC2 significantly enhanced the promoter activity of p21. Importantly, PSMC2 knockdown-induced phenotypes were also rescued by downregulation of P21. Taken together, our data suggest that PSMC2 promotes HCC cell proliferation and cell cycle progression through the p21/cyclin D1 signaling pathway and could be a promising diagnostic and therapeutic target for HCC patients.

Gene Signatures and Prognostic Values of m6A Regulators in Hepatocellular Carcinoma.

N6-methyladenosine (m6A) is the most abundant mRNA modification in mammals and has been implicated in various biological processes. However, its role in hepatocellular carcinoma (HCC) remains largely unknown. In this study, we investigated the alterations of 19 main m6A regulatory genes in HCC and their association with clinicopathological features, including survival. The mutation, copy number variation (CNV) and clinical data of HCC patients were retrieved from The Cancer Genome Atlas (TCGA) database. We found that the m6A regulators had high frequent alterations in HCC. The alterations of m6A regulators were significantly associated with clinicopathological features as well as TP53 alteration. Patients with any mutation of the m6A regulatory genes had worse overall survival (OS) and disease free survival (DFS). Deletion of METTL16 or ALKBH5 predicted poor OS and DFS of HCC patients. Moreover, deletion of METTL16 was an independent risk factor for DFS. Low METT16 expression was association with activation of multiple metabolic pathways in HCC. Finally, by RT-PCR, we confirmed that METTL16 was downregulated in HCC, and that lower METTL16 expression was associated with poor OS. In conclusion, we reported a significant association between alterations of m6A regulators and clinicopathological features, and highlighted the importance of METTL16 among the 19 m6A regulators in HCC pathogenesis. These findings will provide new insights into the role of m6A modification in HCC.