Prognostic Indicator For Hepatocellular Carcinoma Patients Research Articles

BCAR3 and BCAR3-related competing endogenous RNA expression in hepatocellular carcinoma and their prognostic value.

Hepatocellular carcinoma (HCC) is a malignant tumor that has a high incidence and mortality worldwide. Despite extensive studies, the detailed molecular mechanism of HCC development remains unclear. Studies have shown that the occurrence and development of HCC are closely related to abnormal gene expression. BCAR3 has been shown to be overexpressed in a variety of malignant tumors. However, the role of BCAR3 in HCC remains unclear. To investigate the expression of BCAR3 and BCAR3-related competing endogenous RNAs (ceRNAs) in HCC and their clinical significance, in order to provide new ideas for the diagnosis and treatment of HCC. The data of HCC were obtained from the Cancer Genome Atlas database and The Genotype Tissue Expression, including transcriptome data and clinical information. Multiple common databases, including UALCAN, Timer 2.0, cBioPortal, LinkedOmics, starBase, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, were used to analyse the expression of BCAR3, prognostic value, genetic alteration, co-expressed genes, differentially expressed genes, BCAR3 gene-related ceRNAs and functional enrichment analysis in HCC patients. Kaplan-Meier analysis, univariate and multivariate Cox regression analysis were used to analyze survival prognosis and the Spearman test was used to measure correlations between BCAR3 and immune functions. And R language package was used to analyze the correlation between BCAR3 and immune invasion of HCC. Our study indicated that BCAR3 was differentially expressed in various tumor tissues. The over-expression of BCAR3 gene was an unfavorable prognostic indicator for HCC patients, and associated with unfavorable cytogenetic risk and gene mutations. Moreover, most immune cells were positively correlated with BCAR3 (P < 0.05). According to the results of functional enrichment analysis, BCAR3 was involved in the positive regulation of epidermal growth factor receptor signaling pathway and ERBB signaling pathway, and was related to DNA replication and GTPase regulator activity. Finally, our study found that based on RAB30-DT and miR-19b-3p pathways, targeting BCAR3 might promote the occurrence and development of HCC. Collectively, this study indicated that the BCAR3 gene was involved in the occurrence and development of HCC, and it might be a new biomarker and therapeutic target for HCC, but the specific mechanism remains to be further verified.

Comprehensive analysis of m6A reader YTHDF2 prognosis, immune infiltration, and related regulatory networks in hepatocellular carcinoma

BackgroundN6-Methyladenosine (m6A) RNA modification is the most prevalent internal modification pattern in eukaryotic mRNAs and plays critical roles in diverse physiological and pathological processes. However, the expression of m6A regulator YTHDF2, its prognostic value, its biological function, its correlation with tumor microenvironment (TME) immune infiltrates, and related regulatory networks in hepatocellular carcinoma (HCC) remain determined. MethodsTCGA, GTEx, and GEO databases were used to investigate the expression profile of YTHDF2 in HCC. We performed differentially expressed genes (DEGs) analysis and constructed a PPI network to explore the biological processes of YTHDF2 in HCC. Kaplan-Meier curves and Cox regression analysis were used to assess the prognostic value of YTHDF2 and then a clinical prognostic nomogram was constructed. Additionally, ssGSEA was performed to assess the correlation between YTHDF2 and immune infiltration levels. The TISIDB database was applied to explore the expression of YTHDF2 in immune and molecular subtypes of HCC. GSEA identifies the YTHDF2-related signaling pathways. Finally, we utilized miRNet and starBase database to construct regulatory networks for HCC based on lncRNA-miRNA and miRNA-YTHDF2 interactions. ResultsYTHDF2 was significantly upregulated in HCC tumor tissues compared with the adjacent normal tissues. HCC patients in the high YTHDF2 expression group had poorer survival. Multivariate Cox analysis suggested that YTHDF2 may be a new independent prognostic indicator for HCC patients, with the prognostic nomogram exhibiting satisfactory results. YTHDF2 expression was significantly correlated with TME immune cell-infiltrating characteristics. Strong correlations were also shown in immune subtypes, molecular subtypes and immune checkpoints. Further analysis revealed that the combination of YTHDF2 expression and immune cell score was considerably associated with survival outcome in HCC patients. GESA analysis demonstrated that high YTHDF2 expression is associated with multiple biological processes and oncogenic pathways. Moreover, 14 possible regulatory networks were constructed, which are associated with HCC progression. ConclusionOur findings revealed that YTHDF2 may serve as a promising prognostic biomarker for HCC and may regulate the tumor immune microenvironment to provide effective therapeutic strategies.

Development of tryptophan metabolism patterns to predict prognosis and immunotherapeutic responses in hepatocellular carcinoma.

Tryptophan metabolism is associated with tumorigenesis and tumor immune response in various cancers. Liver is the main place where tryptophan catabolism is performed. However, the role of tryptophan metabolism in hepatocellular carcinoma (HCC) has not been well clarified. In the present study, we described the mutations of 42 tryptophan metabolism-related genes (TRPGs) in HCC cohorts. Then, HCC patients were well distributed into two subtypes based on the expression profiles of the 42 TRPGs. The clinicopathological characteristics and tumor microenvironmental landscape of the two subtypes were profiled. We also established a TRPGs scoring system and identified four hallmark TRPGs, including ACSL3, ADH1B, ALDH2, and HADHA. Univariate and multivariate Cox regression analysis revealed that the TRPG signature was an independent prognostic indicator for HCC patients. Besides, the predictive accuracy of the TRPG signature was assessed by the receiver operating characteristic curve (ROC) analysis. These results showed that the TRPG risk model had an excellent capability in predicting survival in both TCGA and GEO HCC cohorts. Moreover, we discovered that the TRPG signature was significantly related to the different immune infiltration and therapeutic drug sensitivity. The functional experiments and immunohistochemistry staining analysis also validated the results above. Our comprehensive analysis enhanced our understanding of TRPGs in HCC. A novel predictive model based on TRPGs was built, which may be considered as a beneficial tool for predicting the clinical outcomes of HCC patients.

The prognostic role of the AST/ALT ratio in hepatocellular carcinoma patients receiving thermal ablation combined with simultaneous TACE

BackgroundTo evaluate the prognostic value of the pre-treatment aspartate transaminase (AST)/alanine transaminase (ALT) ratio in hepatocellular carcinoma (HCC) patients receiving radiofrequency ablation (RFA)/microwave ablation (MWA) combined with simultaneous TACE.MethodsThe data for 117 patients were retrospectively analyzed in this study. The endpoint of prognosis was overall survival (OS). The Youden index was used to choose the optimal cut-off value of the pre-treatment AST/ALT ratio for OS prediction. Univariate and multivariate analyses were used to identify independent risk factors, then integrated to establish the nomogram.ResultsThe AST/ALT ratio cut-off value for OS prediction was 0.89, and patients with a higher AST/ALT ratio had poorer OS. The median OS for the high-value AST/ALT group was not reached, while the median OS for the low-value AST/ALT group was 48.5 months (P = 0.0047). The univariate and multivariate analysis showed that AST/ALT ratio, AFP, and tumor numbers were independent prognostic indicators for OS. The integrated nomogram showed higher predictive accuracy for OS (C-index 0.674, 95%CI: 0.600–0.748).ConclusionsThe preoperative AST/ALT ratio could be a prognostic indicator for HCC patients receiving thermal ablation combined with simultaneous TACE.

Prognostic and Clinical Implications of UNC13C expression in Hepatocellular Carcinoma Patients.

Aberrant expression of UNC13C (Unc-13 Homolog C) has been observed during the progression of oral squamous cell carcinoma. However, the expression pattern and clinical relevance of UNC13C in Hepatocellular carcinoma (HCC) remain to be elucidated. The purpose of this study is to examine UNC13C expression in HCC and explore its role in clinicopathological factor or prognosis in HCC. Two hundred and sixty-five patients diagnosed with HCC were included in the present study. The expression of UNC13C in HCC tissues was analyzed by immunohistochemistry analysis. The relationship between UNC13C protein and clinicopathological characteristics in HCC was investigated. Moreover, the high expression of UNC13C was significantly correlated with T stage, AJCC stage and overall survival rates. Cox regression analysis identified UNC13C as an independent prognostic indicator for HCC patients. UNC13C might be a prognostic biomarker and therapeutic target in HCC. Further studies with larger sample sets are needed to understand the clinical implications of UNC13C in hepatocellular carcinoma.

Liver-specific lncRNA FAM99A may be a tumor suppressor and promising prognostic biomarker in hepatocellular carcinoma

BackgroundIncreasing evidence shows that liver-specific long non-coding RNAs (lncRNAs) play important roles in the development of hepatocellular carcinoma (HCC). We identified a novel liver-specific lncRNA, FAM99A, and examined its clinical significance and biological functions in HCC.MethodsThe expression level and clinical value of FAM99A in HCC were examined using The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and Gene Expression Omnibus (GEO) databases, and were further verified using quantitative real-time polymerase chain reaction (qRT–PCR) in our HCC cohort. Univariate and multivariate Cox proportional hazards regression models were also applied to identify independent prognostic indicators for HCC patients. Cell counting kit-8, colony formation, and Transwell assays were performed to evaluate the effects of FAM99A on the proliferation, migration, and invasion abilities of HCC cells in vitro. A subcutaneous xenograft tumor model was implemented to determine the effect of FAM99A on the tumor growth of HCC cells in vivo. RNA pull-down and mass spectrometry assays were performed to reveal the potential molecular mechanisms of FAM99A in HCC.ResultsThe three public online databases and qRT–PCR data showed that FAM99A was frequently downregulated in HCC tissues and inversely correlated with microvascular invasion and advanced histological grade of HCC patients. Kaplan–Meier survival analysis indicated that decreased FAM99A was significantly associated with poor overall survival of HCC patients based on TCGA database (P = 0.040), ICGC data portal (P < 0.001), and our HCC cohort (P = 0.010). A multivariate Cox proportional hazards regression model based on our HCC cohort suggested that FAM99A was an independent prognostic factor of overall survival for HCC patients (hazard ratio: 0.425, P = 0.039). Upregulation of FAM99A suppressed the proliferation, colony formation, migration, and invasion capacities of HCC cells in vitro, and knockdown of FAM99A had the opposite effects. A subcutaneous xenograft tumor model demonstrated that overexpression of FAM99A significantly inhibited the tumor growth of HCC cells in vivo. Seven tumor-related proteins (PCBP1, SRSF5, SRSF6, YBX1, IGF2BP2, HNRNPK, and HNRNPL) were recognized as possible FAM99A-binding proteins by the RNA pull-down and mass spectrometry assays.ConclusionOur results suggest that FAM99A exerts cancer-inhibiting effects on HCC progression, and it may be a promising prognostic indicator for HCC patients.

Serum T Cell Immunoglobulin Mucin 3 Predicts Worse Prognosis in Hepatocellular Carcinoma Patients Undergoing Transcatheter Arterial Chemoembolization.

BackgroundHepatocellular carcinoma (HCC) is currently a leading cause of cancer-related death, and its prognostic evaluation remains a challenge. We aimed to explore the predictive value of T cell immunoglobulin and mucin 3 (Tim-3) in HCC patients undergoing transcatheter arterial chemoembolization (TACE).Material/MethodsFor the present study, 167 HCC patients who had undergone TACE were retrospectively recruited and randomly stratified into 2 subgroups at a ratio of about 2: 1 (training: 109; validation: 58) using EXCEL software. Pre-TACE serum was collected from all of these patients, and in a second visit a month after the initial treatment, an additional serum sample was collected from 45 patients in the training set. Tim-3 concentrations were determined by enzyme-linked immunosorbent assay. Kaplan-Meier survival curves analysis, log-rank tests, and Cox proportional hazard regression model were applied to evaluate prognostic significance.ResultsPatients whose cancer progressed after TACE had significantly higher serum Tim-3 in both the training and validation sets (both P<0.05). Kaplan-Meier analysis revealed that patients with elevated serum Tim-3 had significantly shorter time-to-progression and overall survival in both the training and validation sets (both P<0.05). Multivariate Cox regression analysis confirmed that elevated pre-TACE Tim-3 served as a novel, independent indicator for predicting poor prognosis in HCC [progression, hazard ratio (HR) 2.197; 95% confidential interval (CI) 1.408–3.373; P<0.001; death, HR 2.570; 95% CI 1.508–4.378; P=0.001], which was further verified in the validation set (progression P=0.005; death P=0.043). Interestingly, serum Tim-3 retained its prognostic significance in the α-fetoprotein-negative subgroup. Notably, patients with high Tim-3 levels after TACE encountered dismal outcomes.ConclusionsSerum Tim-3 might be a satisfactory prognostic indicator for HCC patients undergoing TACE.

Prognostic value of inflammation-immunity-nutrition score in patients with hepatocellular carcinoma treated with anti-PD-1 therapy.

BackgroundThere are no validated biomarkers that can predict the clinical benefit of immune checkpoint blockers against the programmed cell death protein 1 (PD‐1) treatments in hepatocellular carcinoma (HCC). This study aimed to investigate the prognostic value of inflammation‐immunity‐nutrition score (IINS) in patients with HCC treated with anti‐PD‐1 therapy.MethodsA consecutive series of 101 HCC patients treated with PD‐1 inhibitors in Sichuan Provincial People's Hospital between January 2018 and August 2020 were enrolled in the retrospective study. IINS (0–6) was constructed based on pretreatment high‐sensitivity C‐reactive protein (hsCRP), lymphocyte (LYM), and albumin (ALB). The patients were divided into high and low IINS groups according to IINS values. Prognostic values of each variable were evaluated with univariate and multivariate time‐dependent Cox regression analyses. Survival curves were calculated and compared using the Kaplan–Meier method and log‐rank test. The prognostic performance of IINS was further compared with that of other traditional prognostic indicators by receiver operating characteristic (ROC) curve and the areas under the ROC curve.ResultsPatients with low IINS had longer overall survival (OS) (HR: 4.711, 95% CI: 1.80–12.37, p = .001) and progression‐free survival (HR: 3.411, 95% CI: 1.79–6.51, p < .0001) than those with high IINS. The multivariate analysis identified IINS (HR: 3.746, 95% CI: 1.05–13.38, p = .042) and tumor number (HR: 5.111, 95% CI: 1.075–24.299, p = .04) as independent prognostic factors. According to ROC analysis, IINS (AUC =0.729, 95% CI: 0.597–0.861, p = .002) presented better prognostic performance than other traditional prognostic indicators. The area of the IINS‐CA19‐9 under the ROC curve (AUC) was higher than that of the IINS or CA19‐9 levels for the prediction of OS.ConclusionThe results suggest that IINS may be an independent prognostic indicator for HCC patients treated with anti‐PD‐1 therapy. IINS‐CA19‐9 classification may be more effective in predicting clinical benefit of anti‐PD‐1 therapy in HCC patients.

Development of an Autophagy-Based and Stemness-Correlated Prognostic Model for Hepatocellular Carcinoma Using Bulk and Single-Cell RNA-Sequencing.

Accumulating evidence has proved that autophagy serves as a tumor promoter in formed malignancies, and the autophagy-related prognostic signatures have been constructed as clinical tools to predict prognosis in many high-mortality cancers. Autophagy-related genes have participated in the development and metastasis of hepatocellular carcinoma (HCC), but the understanding of their prognostic value is limited. Thereafter, LIMMA and survival analysis were conducted in both ICGC and TCGA databases and a total of 10 hub autophagy-related genes, namely, NPC1, CDKN2A, RPTOR, SPHK1, HGS, BIRC5, SPNS1, BAK1, ATIC, and MAPK3, were collected. Then, GO, KEGG, correlation, consensus, and PCA analyses were utilized to reveal their potential targeted role in HCC treatment. Single-cell RNA-seq of cancer stem cells also indicated that there was a positive correlation between these genes and stemness. In parallel, we applied univariate, LASSO, and multivariate regression analyses to study the autophagy-related genes and finally proposed that ATIC and BIRC5 were the valuable prognostic indicators of HCC. The signature based on ATIC and BIRC5 exhibited moderate power for predicting the survival of HCC in the ICGC cohort, and its efficacy was further validated in the TCGA cohort. Taken together, we suggested that 10 aforementioned hub genes are promising therapeutic targets of HCC and the ATIC/BIRC5 prognostic signature is a practical prognostic indicator for HCC patients.

Down-regulation of MYH10 driven by chromosome 17p13.1 deletion promotes hepatocellular carcinoma metastasis through activation of the EGFR pathway.

Somatic copy number alterations (CNAs) are a genomic hallmark of cancers. Among them, the chromosome 17p13.1 deletions are recurrent in hepatocellular carcinoma (HCC). Here, utilizing an integrative omics analysis, we screened out a novel tumour suppressor gene within 17p13.1, myosin heavy chain 10 (MYH10). We observed frequent deletions (~38%) and significant down‐regulation of MYH10 in primary HCC tissues. Deletion or decreased expression of MYH10 was a potential indicator of poor outcomes in HCC patients. Knockdown of MYH10 significantly promotes HCC cell migration and invasion in vitro, and overexpression of MYH10 exhibits opposite effects. Further, inhibition of MYH10 markedly potentiates HCC metastasis in vivo. We preliminarily elucidated the mechanism by which loss of MYH10 promotes HCC metastasis by facilitating EGFR pathway activation. In conclusion, our study suggests that MYH10, a candidate target gene for 17p13 deletion, acts as a tumour suppressor and may serve as a potential prognostic indicator for HCC patients.

The lymphocyte-C-reactive protein ratio as the optimal inflammation-based score in patients with hepatocellular carcinoma underwent TACE

The lymphocyte-C-reactive protein ratio (LCR) is a recently described inflammation-based score, and it remains unclear which is the optimal inflammation-based score among patients with hepatocellular carcinoma (HCC) who underwent transarterial chemoembolization (TACE). A large cohort of HCC patients (n=1625) who underwent TACE as the initial treatment were enrolled in the present study. Inflammation-based scores, including the Glasgow Prognostic Score (GPS), modified Glasgow Prognostic Score (mGPS), high-sensitivity modified Glasgow Prognostic Score (Hs-mGPS), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), prognostic nutritional index (PNI), systemic immune-inflammation index (SII), and LCR, were all related to the survival of HCC patients, but only the LCR score was a significant and independent predictor in multivariate analysis (hazard ratio: 1.45; 95% confidence interval: 1.27-1.65; P<0.001). Further analysis showed that the LCR score stably and consistently differentiated subgroup patients with distinct prognoses. The predictive accuracies of the LCR score (0.70, 0.68, and 0.68 for 1-, 3-, and 5-year C-index, respectively) were superior to the other inflammatory-based scores (0.60-0.64, 0.58-0.62, and 0.58-0.62 for 1-, 3-, and 5-year C-index, respectively). The LCR score was an independent prognostic indicator for HCC patients who underwent TACE, and it was superior to the other inflammation-based scores in prognostic ability.

Construction and validation of a three-microRNA signature as prognostic biomarker in patients with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), a common type of primary liver cancer, is one of the most aggressive malignant tumors worldwide. Although overall survival (OS) rates for HCC has significantly improved in recent years, however, the exact predictive value of microRNA (miRNA) for the prognosis of HCC has not yet been recognized. Here, we aimed to identify potential prognostic miRNAs involved in HCC by bioinformatics analysis and validated expression levels through quantitative polymerase chain reaction (qPCR) and GEO database. The RNA expression profiles and corresponding clinical information of HCC were available from The Cancer Genome Atlas (TCGA) datasets. Differentially expression and standardization analysis of miRNAs, Kaplan-Meier curve and time dependent ROC curve were performed by using R tools. Differentially expressed miRNAs (DEmiRNAs) and clinical parameters involved in the OS of HCC were confirmed by Cox regression models. And functional enrichment analysis was used to establish functions of the targeted genes of DEmiRNAs. A total of 300 DEmiRNAs were significantly related with HCC, of which 40 were down-regulated and 260 were up-regulated. A total of 344 patients with DEmiRNAs, status, overall survival (OS) time were randomized into training group (172) and test group (172). Multivariate Cox regression analyses revealed that 3 miRNA (hsa-miR-139-3p, hsa-miR-760, hsa-miR-7-5p) had independent prognostic significance for the OS of HCC in both training and test group. Moreover, according to Kaplan Meier analysis, the OS of HCC patients with high-risk score was shorter in validation and entire series. The time dependent ROC curve demonstrated high accuracy of the signature for OS. Besides, target genes of three miRNAs were analyzed by functional enrichment analysis and 20 genes associated with OS were verified by using Kaplan-Meier method. Compared with normal and benign group, the relative expression level of hsa-miR-139-3p was significantly decreased, while hsa-miR-7-5p and hsa-miR-760 were distinctly increased in the plasma of HCC patients. The same results were observed in the independent cohort. Collectively, our research suggested that three-miRNA signature could serve as an independent prognostic indicator for HCC patients.

CD13 promotes hepatocellular carcinogenesis and sorafenib resistance by activating HDAC5-LSD1-NF-κB oncogenic signaling.

RationaleCD13 is a new marker for liver cancer stem cells (CSCs) that contributes to sorafenib resistance in hepatocellular carcinoma (HCC). However, the underlying mechanism of CD13 in HCC sorafenib resistance remains enigmatic.MethodsThe expression of CD13 in HCC cell lines and tissues was assayed by RT‐PCR, western‐blot, and immunohistochemistry staining. Athymic BALB/c nu/nu mice model was used to study the in vivo functions of CD13. Clinical significance of CD13 was evaluated by Kaplan‐Meier methods. Cellular proliferation rate was evaluated by cell counting kit‐8 cell proliferation assay and colony formation assay. Tunel assay was used to detect cell death ratio. Transwell assay was used to evaluate the motility of cells. Immunoprecipitation (IP), liquid chromatography‐mass spectrometry (LC‐MS)/MS, and co‐IP were applied to investigate potential protein interactions of CD13.ResultsIn this research, we found that CD13 expression was higher in metastatic HCC samples, and its overexpression was predicted worse prognosis for patients after surgical resection. Functionally, CD13 promoted HCC proliferation, invasion, cell cycle progression as well as sorafenib resistance. Mechanistically, CD13 interacted with histone deacetylase5 (HDAC5) to promote its protein stability, thus resulting in HDAC5‐mediated lysine‐specific demethylase 1 (LSD1) deacetylation and protein stabilization. Consequently, LSD1 decreased the NF‐κB catalytic unit p65 methylation that led to p65 protein stability. A CD13 inhibitor ubenimex in combination with sorafenib, suppressed the tumor growth and attenuated the resistance of HCC cells toward sorafenib in patient‐derived xenograft models.ConclusionsCD13 promotes HCC progression and induces sorafenib resistance, mainly via interacting with HDAC5 to prevent the degradation of p65 and activate NF‐kB signaling pathway. CD13 is a prognostic indicator for HCC patients underwent curative resection as well as a predictor of response to treatment with sorafenib. Our study establishes the new therapeutic potential of targeting CD13‐HDAC5‐LSD1‐NF‐κB in HCC.

Construction of a prognosis-predicting model based on autophagy-related genes for hepatocellular carcinoma (HCC) patients.

Background: Autophagy, a highly conserved cellular catabolic process by which the eukaryotic cells deliver autophagosomes engulfing cellular proteins and organelles to lysosomes for degradation, is critical for maintaining cellular homeostasis in response to various signals and nutrient stresses. The dysregulation of autophagy has been noted in the pathogenesis of cancers. Our study aims to investigate the prognosis-predicting value of autophagy-related genes (ARG) in hepatocellular carcinoma (HCC).Results: The signature was constructed based on eight ARGs, which stratified HCC patients into high- and low-risk groups in terms of overall survival (OS) (Hazard Ratio, HR=4.641, 95% Confidential Interval, CI, 3.365-5.917, P=0.000). The ARG signature is an independent prognostic indicator for HCC patients (HR = 1.286, 95% CI, 1.194-1.385; P < 0.001). The area under the receiver operating characteristic (ROC) curve (AUC) for 5-year survival is 0.765.Conclusion: This study provides a potential prognostic signature for predicting the prognosis of HCC patients and molecular insights into the significance of autophagy in HCC.Methods: Sixty-two differentially expressed ARGs and the clinical characteristics and basic information of the 369 enrolled HCC patients were retrieved from The Cancer Genome Atlas (TCGA) database. the Cox proportional hazard regression analysis was adopted to identify survival-related ARGs, based on which a prognosis predicting signature was constructed.

Upregulation of Excision Repair Cross-Complementation Group 6-Like (ERCC6L) Promotes Tumor Growth in Hepatocellular Carcinoma.

Excision repair cross-complementation group 6-like (ERCC6L) is overexpressed in some malignancies; however, its role in hepatocellular carcinoma (HCC) remains to be further investigated. In the present study, we explored the expression and function of ERCC6L in HCC. We investigated the expression of ERCC6L by microarray analysis, using the Cancer Genome Atlas database, and by HCC tissue microarray. The results showed that ERCC6L expression was upregulated in tumor specimens and HCC cell lines. High ERCC6L expression in tumor tissues was significantly correlated with poor prognosis and could serve as an independent prognostic indicator for HCC patients. Results of in vitro and in vivo assays revealed that ERCC6L substantially promoted cell proliferation, and our flow cytometry analysis revealed that this was accomplished by acceleration of the G1/S transition. Finally, gene set enrichment analysis and western blotting results indicated that ERCC6L might regulate HCC proliferation by activating p53 signaling. Our study suggests that ERCC6L plays an important role in HCC proliferation and that it might serve as a promising therapeutic target in HCC.

Clusterin role in hepatocellular carcinoma patients treated with oxaliplatin.

Aim: To explore the prognostic value of clusterin (CLU) in hepatocellular carcinoma (HCC) patients treated with oxaliplatin (OXA).Methods: Relative expression of plasma CLU mRNA was examined via fluorescence quantitative real-time PCR (qRT-PCR), and CLU protein level in tissue samples was detected through immunohistochemistry. Chi-square test was used to analyze the relationship between CLU mRNA expression and clinical features of HCC patients treated with OXA. Kaplan–Meier method was performed to assess overall survival for the patients, and prognostic value of CLU in HCC patients was estimated via Cox regression analysis.Results: CLU expression in plasma and tissue specimens was significantly higher among HCC patients than in non-malignant controls (P < 0.001 for both). Moreover, elevated CLU mRNA was closely related to tumor stage, lymph node metastasis and response to OXA (P < 0.05). HCC patients with high CLU expression showed poor response to OXA. In addition, low CLU levels predicted long overall survival time among the study subjects (20.8 vs. 36.6 months, P < 0.001). CLU was an independent prognostic indicator for HCC patients treated with OXA (HR = 2.587, 95%CI = 1.749–3.828, P < 0.001).Conclusion: CLU may be a novel prognostic marker for HCC patients treated with OXA.

Red Cell Distribution Width as a Prognostic Factor in Patients with Hepatocellular Carcinoma.

The red blood cell distribution width (RDW) was reported to be related to the severity of liver diseases, but its clinical significance in patients with hepatocellular carcinoma (HCC) remains unclear. The aim of this study was to explore the clinical significance of RDW in HCC patients. For the retrospective study, 422 HCC patients were enrolled in this study. Hematological parameters and liver biochemical indexes were analyzed. Child-Pugh grade and Barcelona Clinic Liver Cancer (BCLC) stages of the HCC patients were calculated. The diagnostic accuracy was evaluated according to the area under the receiver operating characteristic (ROC) curve. The medical records of HCC patients who were admitted to The Second Affiliated Hospital of Nanjing University of Chinese Medicine from January 2006 to August 2015 were retro-spectively reviewed. Subgroup analysis showed that RDW level of HCC patients with tumor size more than 10 cm were higher than those of HCC patients with tumor size smaller than 3 cm, 3 - 5 cm, and 5 - 10 cm (14.77 ± 2.35%, 15.27 ± 2.65%, 15.32 ± 2.40% vs. 15.97 ± 2.39%, p < 0.001). RDW level significantly increased with worsening Child-Pugh grade and BCLC stages. In addition, RDW level were negatively correlated with red blood cell (RBC) counts, hematocrit (HCT), lymphocyte (LY) counts, hemoglobin (Hb), blood platelet (PLT) counts, and positively correlated with aspartate-aminotransferase (AST), and total bile acid (TBA). ROC curve analysis showed that RDW level was 14.15% was the optimal prognostic cutoff point to determine the survival rate of HCC patients. In the univariate analysis followed by multivariate analysis, RDW level below 14.15% together with better Child-Pugh grade, better BCLC stages, and smaller tumor size were prognostic indicators for HCC patients. This indicated HCC patients with RDW level below 14.15% [hazard ratio of 0.530 (95% confidence interval, 0.395 - 0.710; p < 0.001)] had the lower mortality. RDW level was positively associated with tumor size. The prognosis was better for HCC patients with RDW levels below14.15% together with better Child-Pugh grade, better BCLC stages, and smaller tumor lesions. It suggested RDW level might be an easily obtainable and inexpensive prognostic indicator for HCC patients.

Monoacylglycerol lipase high expression as an independent indicator of survival for patients with hepatocellular carcinoma

Objective: To study the expression level of monoacylglycerol lipase (MAGL) in liver tissues of patients with hepatocellular carcinoma (HCC), and its clinical correlation. Methods: Immunohistochemistry was employed to detect MAGL protein in 353 cases with hepatocellular carcinoma (HCC) and tissue microarray (TMA) for paracancerous liver tissues. The expression levels of MAGL in TMA were quantitatively analyzed using Image-Pro plus 6.0. The difference in MAGL expression between liver cancer tissues and paracancerous liver tissues was compared. Combined with the clinical follow-up data of TMA patients, the correlation between the expression of MAGL in TMA and the degree of HCC tumors differentiation and the survival rate of 1-year and 3-year were analyzed using Logistic regression analysis. The survival curves of patients with different levels of MAGL protein was plotted and analyzed using Kaplan-Meier method. The expression of MAGL protein was analyzed by multiple linear regression analysis. COX regression was used to analyze the correlation between MAGL protein expression level and the risk of HCC death in the included patients. Results: The expression of MAGL in HCC tissues was significantly higher than paracancerous liver tissues. The expression level of MAGL was correlated to the degrees of HCC tumors differentiation (P < 0.001) and 1-year survival rate (P = 0.01), but not with 3-year survival rate (P = 0.91). Survival curve showed that the expression level of MAGL was negatively correlated with prognosis and survival of HCC patients (P = 0.001). Multiple linear regressions showed a negative correlation between MAGL expression level and overall survival time of HCC patients (P=0.010, R2=0.166, Durbin-Watson value: 1.989). COX regression showed that the expression of MAGL was a risk factor for death of patients with HCC [P = 0.004, Exp (B) = 1.000]. Conclusion: The expression level of MAGL has positive correlation with the malignant degree in HCC patients, and negative correlation with its prognosis. Therefore, MAGL may serve as a new prognostic indicator for HCC patients.

A P53-related microRNA model for predicting the prognosis of hepatocellular carcinoma patients.

Studies have shown that microRNAs (miRNAs) play a vital role in tumor progression and patients' prognosis. Therefore, we aimed to construct a miRNA model for forecasting the survival of hepatocellular carcinoma (HCC) patients. The gene expression data of 433 patients with HCC from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus public databases were remined by survival analysis and receptor manipulation characteristic curve (ROC). A prognostic model including six miRNAs (hsa-mir-26a-1-3p, hsa-mir-188-5p, hsa-mir-212-5p, hsa-mir-149-5p, hsa-mir-105-5p, and hsa-mir-132-5p) were constructed in the training dataset (TCGA, n = 333). HCC patients were stratified into a high-risk group and a low-risk group with significantly different survival (median: 2.75 vs. 8.93 years, log-rank test p < .001). Then we proved its performance of stratification in another independent dataset (GSE116182, median: 2.55 vs 6.96 years, log-rank test p = .008). Cox regression analysis showed that the prognostic model was an independent prognostic indicator for HCC patients. Then time-dependent ROC analyses were performed to test the prognostic ability of the model with that of TNM staging, we found the model had a better performance, especially at 5 years (AUC = 0.76). Functional prediction showed that the genes targeted by the six prognostic miRNAs in the prognostic model were highly expressed in the P53-related pathway. In conclusion, we constructed a prognostic miRNA model that could indicate the survival of HCC patients.

Identification of prognostic markers for hepatocellular carcinoma based on miRNA expression profiles

AimsThe aim of the study was to identify key miRNAs related to hepatocellular carcinoma (HCC) and then to explore their potential function and clinical significance. Materials and methodsThe miRNA expression profiles of 387 HCC and 62 normal liver tissues were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. GEO2R tool and edgeR package in R/Bioconductor were used to screen out HCC-related miRNAs. VennDiagram package was used to identify key miRNAs related to HCC. The miRWalk tool and multiple R packages, such as pROC and survival, were used to explore potential function and clinical significance of these key miRNAs. Key findingsA total of 17 and 300 HCC-related human miRNAs were identified in GEO dataset and TCGA, respectively. Thereinto seven miRNAs including hsa-miR-199a-3p, hsa-miR-199b-3p, hsa-miR-139-5p, hsa-miR-139-3p, hsa-miR-424-3p, hsa-miR-1269b and hsa-miR-1269a were key miRNAs related to HCC. Functional enrichment analysis showed that these key miRNAs were involved in multiple biological processes, such as telomere maintenance via telomerase, protein sumoylation, histone mRNA metabolic process and angiotensin maturation. Cox regression analysis indicated that hsa-miR-139-5p expression was associated with the prognosis of HCC patients. ROC curve analysis suggested that survival prediction model developed based on tumor stage and hsa-miR-139-5p exhibited good performance in predicting 3-year overall survival of HCC patients. SignificanceThe present study identified several HCC-related miRNAs, which might serve as new diagnostic markers and therapeutic targets for HCC. In addition, hsa-miR-139-5p might act as a promising prognostic indicator for HCC patients.