Overall Survival Of Hepatocellular Carcinoma Patients Research Articles

Long noncoding RNA LINC01132 enhances immunosuppression and therapy resistance via NRF1/DPP4 axis in hepatocellular carcinoma

BackgroundLong noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression and play fundamental roles in various types of cancer. Current developments in transcriptome analyses unveiled the existence of lncRNAs; however, their functional characterization remains a challenge.MethodsA bioinformatics screen was performed by integration of multiple omics data in hepatocellular carcinoma (HCC) prioritizing a novel oncogenic lncRNA, LINC01132. Expression of LINC01132 in HCC and control tissues was validated by qRT-PCR. Cell viability and migration activity was examined by MTT and transwell assays. Finally, our results were confirmed in vivo mouse model and ex vivo patient derived tumor xenograft experiments to determine the mechanism of action and explore LINC01132-targeted immunotherapy.ResultsSystematic investigation of lncRNAs genome-wide expression patterns revealed LINC01132 as an oncogene in HCC. LINC01132 is significantly overexpressed in tumor and associated with poor overall survival of HCC patients, which is mainly driven by copy number amplification. Functionally, LINC01132 overexpression promoted cell growth, proliferation, invasion and metastasis in vitro and in vivo. Mechanistically, LINC01132 acts as an oncogenic driver by physically interacting with NRF and enhancing the expression of DPP4. Notably, LINC01132 silencing triggers CD8+ T cells infiltration, and LINC01132 knockdown combined with anti-PDL1 treatment improves antitumor immunity, which may prove a new combination therapy in HCC.ConclusionsLINC01132 functions as an oncogenic driver that induces HCC development via the NRF1/DPP4 axis. Silencing LINC01132 may enhance the efficacy of anti-PDL1 immunotherapy in HCC patients.

RPS3 predicts poor overall survival in HBV-related hepatocellular carcinoma patients: a data-mining with LASSO-regression algorithm.

This analysis aimed to investigate the candidate biomarkers associated with overall survival (OS) in hepatocellular carcinoma (HCC) patients. In the GSE14520 dataset, candidate parameters were selected and included in the Cox regression and Nomogram models through bioinformatic enrichment methods and LASSO analysis, survivor functions of candidate biomarkers were also assessed. Complement and coagulation cascades including 36 differential expressed genes (DEGs) and ribosome pathway including 27 DEGs were significantly enriched (both p < 0.05 and adjusted p < 0.05). LASSO model, Cox regression and nomogram analysis indicated that RPS3, together with BCLC and TNM staging, were significantly associated with OS in HCC patients. Validated in the GEO series, TCGA and Human Protein Atlas (HPA) datasets, RPS3 mRNA and RPS3 protein were significantly upregulated in tumor tissues compared to that in nontumor tissues (all p < 0.05). Upregulation of RPS3 has been linked to high alpha fetoprotein (AFP), advanced tumor stages and multinodular (all p < 0.05). After adjusting AFP, tumor stage and multinodular, log rank analysis revealed that HCC patients with high RPS3 had unfavorable OS compared to those with low RPS3 (all p < 0.05). RPS3 upregulation in tumors might contribute to unfavorable OS in HCC patients.

Ferroptosis: From Basic Research to Clinical Therapeutics in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common and highly heterogeneous malignancies worldwide. Despite the rapid development of multidisciplinary treatment and personalized precision medicine strategies, the overall survival of HCC patients remains poor. The limited survival benefit may be attributed to difficulty in early diagnosis, the high recurrence rate and high tumor heterogeneity. Ferroptosis, a novel mode of cell death driven by iron-dependent lipid peroxidation, has been implicated in the development and therapeutic response of various tumors, including HCC. In this review, we discuss the regulatory network of ferroptosis, describe the crosstalk between ferroptosis and HCC-related signaling pathways, and elucidate the potential role of ferroptosis in various treatment modalities for HCC, such as systemic therapy, radiotherapy, immunotherapy, interventional therapy and nanotherapy, and applications in the diagnosis and prognosis of HCC, to provide a theoretical basis for the diagnosis and treatment of HCC to effectively improve the survival of HCC patients.

Intraoperative low-dose dopamine is associated with worse survival in patients with hepatocellular carcinoma: A propensity score matching analysis.

BackgroundDopamine is widely used in patients during surgery. We evaluated the association between intraoperative low-dose dopamine administration and recurrence-free survival (RFS) and overall survival (OS) in patients with hepatocellular carcinoma (HCC).MethodsConsecutive patients with nonmetastatic HCC who underwent radical hepatectomy were enrolled between 2008 and 2010. Univariate and multivariate logistic regression analyses were used to evaluate the prognostic factors for RFS and OS. Survival outcomes were evaluated using Kaplan–Meier analyses with the log-rank test. A one-to-one propensity score matching (PSM) analysis was performed to reduce confounding bias.ResultsA total of 805 HCC patients, including 699 patients who did not receive dopamine consumption and 106 patients who received low-dose dopamine during the operation, were retrospectively analyzed. The patients who were assigned low-dose dopamine had worse RFS (p = 0.009) and OS (p = 0.041) than those who did not receive dopamine. Multivariate regression analysis showed that the intraoperative administration of low-dose dopamine was an independent unfavorable predictor for RFS (p = 0.004) but not for OS (p = 0.059). After PSM, the low-dose dopamine-treated group still had significantly poorer RFS (p = 0.003) and OS (p = 0.002). When stratified by time of recurrence, patients with low-dose dopamine use had a significantly greater chance of recurrence within 2 years (p = 0.007) but not after 2 years (p = 0.186).ConclusionsIntraoperative low-dose dopamine use has a negative impact on RFS and OS in HCC patients who have undergone radical hepatectomy. Further prospective studies are required to assess the effects of low-dose dopamine on surgical outcomes in HCC patients.

Comprehensive analysis of nine m7G-related lncRNAs as prognosis factors in tumor immune microenvironment of hepatocellular carcinoma and experimental validation.

Background: Hepatocellular carcinoma (HCC) remains the most prevalent gastrointestinal malignancy worldwide, with robust drug resistance to therapy. N7-methylguanosine (m7G) mRNA modification has been significantly related to massive human diseases. Considering the effect of m7G-modified long non-coding RNAs (lncRNAs) in HCC progression is unknown, the study aims at investigating a prognostic signature to improve clinical outcomes for patients with HCC. Methods: Two independent databases (TCGA and ICGC) were used to analyze RNAseq data of HCC patients. First, co-expression analysis was applied to obtain the m7G-related lncRNAs. Moreover, consensus clustering analysis was employed to divide HCC patients into clusters. Then, using least absolute shrinkage and selection operator-Cox regression analysis, the m7G-related lncRNA prognostic signature (m7G-LPS) was first tested in the training set and then confirmed in both the testing and ICGC sets. The expression levels of the nine lncRNAs were further confirmed via real-time PCR in cell lines, principal component analysis, and receiver operating characteristic curve. The m7G-LPS could divide HCC patients into two different risk groups with the optimal risk score. Then, Kaplan–Meier curves, tumor mutation burden (TMB), therapeutic effects of chemotherapy agents, and expressions of immune checkpoints were performed to further enhance the availability of immunotherapeutic treatments for HCC patients. Results: A total of 1465 lncRNAs associated with the m7G genes were finally selected from the TCGA database, and through the univariate Cox regression, the expression levels of 22 m7G-related lncRNAs were concerning HCC patients’ overall survival (OS). Then, the whole patients were grouped into two subgroups, and the OS in Cluster 1 was longer than that of patients in Cluster 2. Furthermore, nine prognostic m7G-related lncRNAs were identified to conduct the m7G-LPS, which were further verified. A prognostic nomogram combined age, gender, HCC grade, stage, and m7G-LPS showed strong reliability and accuracy in predicting OS in HCC patients. Finally, immune checkpoint expression, TMB, and several chemotherapy agents were remarkably associated with risk scores. More importantly, the OS of the TMB-high patients was the worst among the four groups. Conclusion: The prognostic model we established was validated by abundant algorithms, which provided a new perspective on HCC tumorigenesis and thus improved individualized treatments for patients.

Identification of G6PC as a potential prognostic biomarker in hepatocellular carcinoma based on bioinformatics analysis.

Hepatocellular carcinoma (HCC) has high mortality and incidence rates around the world with limited therapeutic options. There is an urgent need for identification of novel therapeutic targets and biomarkers for early diagnosis and predicting patient survival with HCC.Several studies (GSE102083, GSE29722, GSE101685, and GSE112790) from the GEO database in HCC were screened and analyzed by GEO2R, gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were conducted with the Database for Annotation, Visualization and Integrated Discovery. The protein-protein interaction network was plotted and the module analysis was performed using Search Tool for the Retrieval of Inter-acting Genes/Proteins database and Cytoscape. The expression and survival of key genes were identified using UALCAN, Kaplan–Meier Plotter and ONCOMINE online databases, and the immune infiltration level of key genes was analyzed via the Tumor Immune Estimation Resource (TIMER) database.Through database analysis, eight key genes were finally screened out, and the expressions of cyclin-dependent kinase regulatory subunit 2 and glucose-6-phosphatase catalytic (G6PC), which were closely related to the survival of HCC patients, was detected by using UALCAN. Further analysis on the differential expression of G6PC in multiple cancerous tumors and normal tissues revealed low expression in many solid tumors by Oncomine and TIMER. In addition, Kaplan–Meier plotter and UALCAN database analysis to access diseases prognosis suggested that low expression of G6PC was significantly associated with poor overall survival in HCC patients. Finally, TIMER database analysis showed a significant negative correlation between G6PC and infiltration levels of six kinds of immune cells. The somatic copy number alterations of G6PC were associated with B cells, CD8+ T cells, CD4+ T cells, macrophages, dentritic cells and neutrophils.These bioinformatic data identified G6PC as a potential key gene in the diagnosis and prognosis of HCC.

High expression of nectin-1 indicates a poor prognosis and promotes metastasis in hepatocellular carcinoma.

ObjectivesNectins are a new class of cell-adhesion molecules that play an important role in tumorigenesis and disease progression. The aim of this study was to investigate the prognostic and pathogenetic roles of nectins in hepatocellular carcinoma (HCC).MethodsThe expression levels of the nectin family in HCC and their role in prognosis were analyzed by bioinformatics analysis based on The Cancer Genome Atlas (TCGA) liver hepatocellular carcinoma database. The correlations between nectins and immune cells were analyzed using TIMER. The functional enrichment of the nectin-1 coexpression network was evaluated in TCGA cohort, and the expression levels of nectin-1 were detected by immunohistochemistry and Western blot analysis. A Transwell kit was used for cell migration experiments. Cell proliferation was analyzed using Cell Counting Kit-8.ResultsThe expression levels of nectin-1 protein in the cancer tissues of 28 patients with HCC were higher than those in paracancerous tissues. The Kaplan–Meier plotter analysis showed that the high expression of all nectin family numbers was related to the poor prognosis of HCC patients. The abnormal expression of nectin-1 effectively distinguished the prognosis at different stages and grades of HCC. The high expression of 17 methylation sites of the nectin-1 gene was related to the high overall survival of HCC patients. Kyoto Encyclopedia of Genes and Genomes analysis of genes negatively correlated with nectin-1, revealing their close relation to the regulation of the immune-effector process. Pearson’s correlation analysis showed that nectin-1 was significantly positively correlated with multiple immune genes and B cells, CD4+ T cells, macrophages, neutrophils, and dendritic cell infiltration. Cell proliferation of the knockdown (KD) group decreased significantly compared to the NC-KD group. The number of metastatic cells in the KD group decreased significantly compared to that in the NC-KD group.ConclusionsAbnormal expression of nectins and multiple methylation sites closely correlates with poor prognosis in HCC patients. Nectins are related to immune cell infiltration and immune-related genes. In particular, nectin-1 can promote the proliferation and migration of liver cancer cells and distinguish the prognosis at different stages and grades of HCC. Nectin-1 might be a new potential molecular marker for prognostic evaluation and also a therapeutic target for HCC.

Heat-shock protein 90α is a potential prognostic and predictive biomarker in hepatocellular carcinoma: a large-scale and multicenter study

BackgroundAlthough the diagnostic value of plasma heat-shock protein 90α (HSP90α) in hepatocellular carcinoma (HCC) has been previously reported, the causal effect of the plasma HSP90α levels on HCC prognosis remains largely unclear. To this extent, we sought to assess whether the plasma HSP90α acts as a prognostic factor for HCC patients.MethodsA total of 2150 HCC patients were included in this retrospective study between August 2016 and July 2021. Plasma HSP90α levels were tested within a week before treatment and their association with prognosis was assessed.ResultsAn optimal cutoff value of 143.5 for the HSP90α based on the overall survival (OS) was determined using the X-tile software. HCC patients with HSP90α < 143.5 ng/mL (low HSP90α) before and after propensity score matching (PSM) indicated longer median OS (mOS) relative to those with HSP90α ≥ 143.5 ng/mL (high HSP90α) (37.0 vs. 9.0 months, p < 0.001; 19.2 vs. 9.6 months, p < 0.001; respectively). In addition, the high HSP90α plasma level is an independent poor prognostic factor for OS in HCC patients. In our subgroup analysis, including the supportive care group, surgery group, transarterial chemoembolization (TACE) group, adjuvant TACE group, an immune checkpoint inhibitor (ICI) plus targeted therapy group, and TACE plus ICI group, the high HSP90α group demonstrated better OS compared to the low HSP90α group. Moreover, in the supportive care, TACE, ICI plus targeted therapy, TACE plus ICI groups, and high HSP90α levels were also an independent poor prognostic factors for OS.ConclusionsOur study confirmed that the plasma HSP90α level can be used as a prognostic biomarker for HCC.

The upregulation of stromal antigen 3 expression suppresses the phenotypic hallmarks of hepatocellular carcinoma through the Smad3-CDK4/CDK6-cyclin D1 and CXCR4/RhoA pathways

BackgroundThe stromal antigen 3 (STAG3) gene encodes an adhesion complex subunit that can regulate sister chromatid cohesion during cell division. Chromosome instability caused by STAG3 gene mutation may potentially promote tumor progression, but the effect of STAG3 on hepatocellular carcinoma (HCC) and the related molecular mechanism are not reported in the literature. The mechanism of the occurrence and development of HCC is not adequately understood. Therefore, the biological role of STAG3 in HCC remains to be studied, and whether STAG3 might be a sensitive therapeutic target in HCC remains to be determined.MethodsThe expression and clinical significance of STAG3 in HCC tissues and cell lines were determined by RT–qPCR and immunohistochemistry analyses. The biological functions of STAG3 in HCC were determined through in vitro and in vivo cell function tests. The molecular mechanism of STAG3 in HCC cells was then investigated by western blot assay.ResultsThe mRNA expression of STAG3 was lower in most HCC cells than in normal cells. Subsequently, an immunohistochemical analysis of STAG3 was performed with 126 samples, and lower STAG3 expression was associated with worse overall survival in HCC patients. Moreover, cytofunctional tests revealed that the lentivirus-mediated overexpression of STAG3 in HCC cells inhibited cell proliferation, migration, and invasion; promoted apoptosis; induced G1/S phase arrest in vitro; and inhibited tumor growth in vivo. Furthermore, studies of the molecular mechanism suggested that the overexpression of STAG3 increased Smad3 expression and decreased CDK4, CDK6, cyclin D1, CXCR4 and RhoA expression.ConclusionSTAG3 exhibits anticancer effects against HCC, and these effects involve the Smad3-CDK4/CDK6-cyclin D1 and CXCR4/RhoA pathways. STAG3 is a tumor-suppressor gene that may serve as a potential target for molecular therapy, which provides a new idea for the treatment of HCC.

Construction of a Novel Clinical Stage-Related Gene Signature for Predicting Outcome and Immune Response in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) with high heterogeneity is one of the most frequent malignant tumors. However, there were no studies to create a clinical stage-related gene signature for HCC patients. Differentially expressed genes (DEGs) associated with clinical stage of HCC were analyzed based on TCGA datasets. Functional enrichment analysis was carried out by the use of stage-related DEGs. Then, the least absolute shrinkage and selection operator (LASSO) regression and univariate Cox regression were performed to reduce the overfit and the number of genes for further analysis. Next, survival and ROC assays were carried out to demonstrate the model using TCGA. Functional analysis and immune microenvironment analysis related to stage-related DEGs were performed. Reverse transcriptase polymerase chain reaction (RT-PCR) and Cell Counting Kit-8 (CCK-8) assays were applied to examine the expression and function of PNCK in HCC. In this research, there were 21 DEGs between HCC specimens with stage (I-II) and HCC specimens with stage (III-IV), including 20 increased genes and 1 decreased genes. A novel seven-gene signature (including PITX2, PNCK, GLIS1, SCNN1G, MMP1, ZNF488, and SHISA9) was created for the prediction of outcomes of HCC patients. The ROC curves confirmed the prognostic value of the new model. Cox assays demonstrated that the seven-gene signature can independently forecast overall survival. The immune analysis revealed that patients with low risk score exhibited more immune activities. Moreover, we confirmed that PNCK expressions were distinctly increased in HCC, and its silence suppressed the proliferation of HCC cells. Overall, our research offered a robust and reliable gene signature which displayed an important value in the prediction of overall survival of HCC patients and might deliver more effective personalized therapies.

A Novel Ferroptosis-Related Long Non-Coding RNA Prognostic Signature Correlates With Genomic Heterogeneity, Immunosuppressive Phenotype, and Drug Sensitivity in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) with high heterogeneity is a common malignancy worldwide, but effective treatments are limited. Ferroptosis plays a critical role in tumors as a novel iron-dependent and reactive oxygen species-reliant type of cell death. Several studies have shown that long non-coding RNAs (lncRNAs) can drive HCC initiation and progression. However, the prognostic value of ferroptosis-related lncRNAs in patients with HCC has not been explored comprehensively. Gene set variation analysis (GSVA) based on gene set and RNA-seq profiles obtained from public databases indicated that ferroptosis is suppressed in HCC patients. Ferroptosis-related differentially expressed lncRNAs were screened by Pearson’s test. Univariate Cox regression, least absolute shrinkage and selection operator (LASSO) regression, and multivariate Cox regression were performed to establish a novel five ferroptosis-related lncRNA signature in the training cohort with 60% patients, which was further verified in the testing cohort with 40% patients. Dimensionality reduction analysis, Kaplan–Meier curve, receiver operating characteristic (ROC) curve, independent prognostic analysis, and stratification analysis confirmed that our signature had a high clinical application value in predicting the overall survival of HCC patients. Compared to the clinicopathological factors and the other four published HCC prognostic signatures, the current risk model had a better predictive value. The comparison results of functional enrichment, tumor immune microenvironment, genomic heterogeneity, and drug sensitivity between the high- and low-risk groups showed that the risk score is associated with extensive genomic alterations, immunosuppressive tumor microenvironment, and clinical treatment response. Finally, cell experiments showed that silencing LNCSRLR expression inhibited the growth, proliferation, migration, and invasion of the HCC cell line. Thus, the model can function as an efficient indicator for predicting clinical prognosis and treatment of anticancer drugs in HCC patients.

Elevated Small Nuclear Ribonucleoprotein Polypeptide an Expression Correlated With Poor Prognosis and Immune Infiltrates in Patients With Hepatocellular Carcinoma.

BackgroundElevated Small Nuclear Ribonucleoprotein Polypeptide A (SNRPA) can enhance tumor cell growth and proliferation in various cancers. However, rarely studies focus on the comprehensive analysis of SNRPA in hepatocellular carcinoma (HCC).MethodsTCGA and GEO databases were used to analyze the mRNA expression of SNRPA in HCC. Protein expression of SNAPA was validated using immunohistochemistry. Stably transfected HCC cells were used to investigate the role of SNRPA in the progression of HCC. The functional enrichment analysis was utilized for the biological function prediction. The CIBERSORT and ssGSEA algorithms were used to evaluate the composition of the tumor microenvironment and immunocyte infiltration ratio.ResultsThe SNRPA expression was upregulated in HCC and positively correlated with tumor stage and grade. SNRPA overexpression were independent risk factors for poor overall survival (OS) and recurrence-free survival (RFS). In patients with early-stage disease, low alpha-fetoprotein expression, and better differentiation, SNRPA still exhibited the excellent prognostic value. Knockdown of SNRPA inhibited the proliferation and migration while promoting the apoptosis of HCC cells. Higher methylation of the CpG site cg16596691 correlated with longer OS in HCC patients. Genes co-expressed with SNRPA were overexpressed in HCC and correlated with shorter OS. The GO and KEGG enrichment analysis showed that SNRPA expression was related to mRNA splicing, spliceosome signaling. GSEA demonstrated that the main enrichment pathway of SNRPA-related differential genes was spliceosome signaling, cell cycle signaling, P53 signaling pathway, T cell receptor signaling pathway, natural killer cell-mediated signaling. CIBERSORT and ssGSEA algorithm revealed that SNRPA was mainly associated with the higher proportion of CD8+T cells, T cells follicular helper, T cells regulatory, Macrophages M0, and the lower proportion of T cells CD4 memory resting, NK cells resting, Monocytes, and Mast cells resting.ConclusionElevated SNRPA enhances tumor cell proliferation and correlated with poor prognosis and immune infiltrates in patients with HCC.

The correlation of fibrinogen-like protein-1 expression with the progression and prognosis of hepatocellular carcinoma

BackgroundFibrinogen-like-protein 1 (FGL1), a member of the fibrinogen-related protein (FREP) family, is a major ligand of the immune inhibitory receptor lymphocyte-activation gene 3 (LAG-3). While FGL1 is strongly implicated in the development and prognosis of a variety of diseases, its role in hepatocellular carcinoma (HCC) is still disputed. Therefore, the role of FGL1 expression in the progression and prognosis of HCC was investigated.Methods and resultsIn the present study, bioinformatics analysis was first used to probe the expression profile of FGL1 in multiple malignant tumor tissues and paired normal tissues, and to explore the possible relationship between FGL1 and prognosis of HCC patients. Thereafter, the expression levels of FGL1 were determined and compared in human HCC cell lines, HCC tissues, peri-tumor tissues and normal liver tissues by western blot analysis. Furthermore, tissue microarrays were used to detect the expression of FGL1 through immunohistochemical staining and to verify whether the FGL1 expression level was associated with clinicopathological features and the prognosis of HCC patients. The results showed that FGL1 was downregulated significantly in most of the HCC cells lines and HCC tissues, corresponding to the results of the bioinformatics and western blot analyses. FGL1 expression level in HCC was found to be correlated to Edmondson grade and metastasis of the HCC. Additionally, high FGL1 expression was associated with better overall survival in HCC patients, suggesting that FGL1 could function as a tumor suppressor.ConclusionsThe expression level of FGL1 can be correlated with the progression and prognosis of HCC, suggesting its potential as a prognostic biomarker.

The m6A/m5C/m1A Regulated Gene Signature Predicts the Prognosis and Correlates With the Immune Status of Hepatocellular Carcinoma.

RNA modification of m6A/m5C/m1A contributes to the occurrence and development of cancer. Consequently, this study aimed to investigate the functions of m6A/m5C/m1A regulated genes in the prognosis and immune microenvironment of hepatocellular carcinoma (HCC). The expression levels of 45 m6A/m5C/m1A regulated genes in HCC tissues were determined. The functional mechanisms and protein–protein interaction network of m6A/m5C/m1A regulated genes were investigated. The Cancer Genome Atlas (TCGA) HCC gene set was categorized based on 45 m6A/m5C/m1A regulated genes, and survival analysis was used to determine the relationship between the overall survival of HCC patients in subgroups. Cox and least absolute shrinkage and selection operator (LASSO) regression analyses were used to construct the risk model and nomogram for m6A/m5C/m1A regulated genes. The relationships between m6A/m5C/m1A regulated gene subsets and risk model and immune cell infiltration were analyzed using CIBERSORT. m6A/m5C/m1A regulated genes were involved in mRNA and RNA modifications, mRNA and RNA methylation, mRNA and RNA stability, and other processes. There was a statistically significant difference between cluster1 and cluster2 groups of genes regulated by m6A/m5C/m1A. The prognosis of cluster1 patients was significantly better than that of cluster2 patients. There were statistically significant differences between the two cluster groups in terms of fustat status, grade, clinical stage, and T stage of HCC patients. The risk model comprised the overexpression of YBX1, ZC3H13, YTHDF1, TRMT10C, YTHDF2, RRP8, TRMT6, LRPPRC, and IGF2BP3, which contributed to the poor prognosis of HCC patients. The high-risk score was associated with prognosis, fustat status, grade, clinical stage, T stage, and M stage and was an independent risk factor for poor prognosis in HCC patients. High-risk score mechanisms included spliceosome, RNA degradation, and DNA replication, among others, and high-risk was closely related to stromal score, CD4 memory resting T cells, M0 macrophages, M1 macrophages, resting mast cells, CD4 memory activated T cells, and follicular helper T cells. In conclusion, the cluster subgroup and risk model of m6A/m5C/m1A regulated genes were associated with the poor prognosis and immune microenvironment in HCC and are expected to be the new tools for assessing the prognosis of HCC patients.

G Protein-Coupled Receptor Kinase 4 Is a Novel Prognostic Factor in Hepatocellular Carcinoma

Purpose We previously reported that G protein-coupled receptor kinase (GRK) 4 halts cell cycle progression and induces cellular senescence in HEK293 cells. The present study was aimed at assessing the prognostic value of GRK4 in hepatocellular carcinoma (HCC). Methods GRK4 expression was detected by immunohistochemistry in paired tumoral and peritumoral tissues of 325 HCC patients. One hundred and twenty-six patients from Western China were utilized as a training cohort to develop a nomogram, while 86 patients from Eastern China were used as a validation cohort. The proliferation and migration of lentiviral-GRK4 expressing HepG2 cells were determined by MTT and wound healing assays. Results GRK4 was differentially expressed in HCC tissues. Tumoral GRK4 intensity, tumor type, and T stage were independent prognostic factors and used to form a nomogram for predicting overall survival (OS), which obtained a good concordance index of 0.82 and 0.77 in training and validation cohort, respectively. The positive and negative prediction values with nomogram were, respectively, 83% and 75% in training cohort and 100% and 52% in validation cohort. Patients with nomogram scores > 32 and 78 showed high risk for OS. Proliferation and motility capabilities were significantly restrained in GRK4-overexpressing HCC cells. Discussion. Low GRK4 expression in HCC tumor tissues indicates poor clinical outcomes. A prognostic nomogram including tumoral GRK4 expression would improve the predictive accuracy of OS in HCC patients. We also demonstrated that GRK4 overexpression inhibits proliferation and migration of HCC cells. The molecular mechanism underlying is worth further study.

CircASPH Promotes Hepatocellular Carcinoma Progression Through Methylation and Expression of HAO2.

CircRNAs have been reported to be related to hepatocellular carcinoma (HCC) development. Limited studies have revealed the expression profile of circRNAs in tumor and para-tumor normal samples in HCC patients. We found that circASPH was significantly increased in HCC tumor samples and that the level of circASPH was closely related to the overall survival of HCC patients. Mechanistically, circASPH could regulate the methylation of the promoter and expression of hydrocyanic oxidase 2 (HAO2) to promote HCC progression by acting as a sponge for miR-370-3p, and miR-370-3p could target DNMT3b and increase the 5mC level. In summary, our study determined that circASPH could regulate the methylation and expression of HAO2 and it could be considered an important epigenetic regulator in HCC progression.

DDX55 promotes hepatocellular carcinoma progression by interacting with BRD4 and participating in exosome-mediated cell-cell communication.

The involvement of DEAD‐box helicase 55 (DDX55) in oncogenesis has been suggested, but its biological role in hepatocellular carcinoma (HCC) remains unknown. The present study verified the upregulation of DDX55 in HCC tissues compared with non‐tumor controls. DDX55 displayed the highest prognostic values among the DEAD‐box protein family for recurrence‐free survival and overall survival of HCC patients. In addition, the effects of DDX55 in the promotion of HCC cell proliferation, migration, and invasion were determined ex vivo and in vivo. Mechanistically, we revealed that DDX55 could interact with BRD4 to form a transcriptional regulatory complex that positively regulated PIK3CA transcription. Following that, β‐catenin signaling was activated in a PI3K/Akt/GSK‐3β dependent manner, thus inducing cell cycle progression and epithelial–mesenchymal transition. Intriguingly, both DDX55 mRNA and protein were identified in the exosomes derived from HCC cells. Exosomal DDX55 was implicated in intercellular communication between HCC cells with high or low DDX55 levels and between HCC cells and endothelial cells, thereby promoting the malignant phenotype of HCC cells and angiogenesis. In conclusion, DDX55 may be a valuable prognostic biomarker and therapeutic target in HCC.

Low Psoas-Muscle index is associated with decreased survival in hepatocellular carcinoma treated with transarterial chemoembolization

Purpose Skeletal muscle index (SMI) is a promising predictor of clinical outcomes in patients with malignant diseases. As a simpler surrogate of sarcopenia-psoas muscle index (PMI), its predict value for overall survival (OS) after transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) has not been reported. To determine if changes in the PMI predicted OS in individuals with HCC treated with TACE. Patients and Methods A retrospective analysis was performed in HCC patients treated with TACE between January 2018 and March 2019. The survival curve according to PMI was estimated by the Kaplan–Meier method and then compared by the log-rank test. Cox proportional hazards models were conducted to identify the prognostic factors for OS. Furthermore, the predictive abilities of PMI and SMI were compared by using Harrell’s concordance index (C-index). Results Two hundred and twenty-eight patients (175 men, mean age 59 ± 11 years) were analysed. The OS was less in patients with low PMI than those with high PMI (median OS: 16.9 vs. 38.5 months, p < .001). Multivariate analysis found that either PMI (hazard ratio [HR] = 0.64; 95% confidence interval [CI], 0.45–0.91; p < .001) or SMI (HR = 0.51; 95% CI, 0.36–0.72; p < .001) was significantly associated with OS. In the multivariate analysis, the C-index for PMI was 0.78 and 0.79 for SMI (p = .985). Conclusion PMI is a simple tool to predict OS in HCC patients treated with TACE. The predictive ability of PMI is comparable to that of SMI. Key messages Low psoas-muscle index is associated with decreased overall survival in hepatocellular carcinoma treated with transarterial chemoembolization (TACE). Psoas-muscle index has advantages of being faster and easier to acquire, which thus makes it more likely to achieve widespread clinical application.

Comprehensive Molecular Analyses of a Macrophage-Related Gene Signature With Regard to Prognosis, Immune Features, and Biomarkers for Immunotherapy in Hepatocellular Carcinoma Based on WGCNA and the LASSO Algorithm.

Macrophages have been reported to exert a crucial role in hepatocellular carcinoma (HCC). This study aimed to explore the macrophage-related genes and establish a macrophage-related signature (MRS) model to predict the overall survival (OS) of patients with HCC based on these genes’ expression. We screened the macrophage-related gene module by weighted gene coexpression network analysis (WGCNA), the least absolute shrinkage and selection operator (LASSO) Cox regression analysis was utilized for further selection, and the selected genes were entered into stepwise regression to develop the MRS model, which was further validated in the Gene Expression Omnibus (GEO) and International Cancer Genome Consortium (ICGC) datasets. We analyzed the biological phenotypes associated with macrophages in terms of functional enrichment, tumor immune signature, and tumor mutational signature. The patient’s response to immunotherapy was inferred by the tumor immune dysfunction and exclusion (TIDE) score, the immunophenotype score (IPS), and the IMvigor210 dataset. A novel MRS model was established based on the LASSO regression coefficients of the genes PON1, IL15RA, NEIL3, HILPDA, PFN2, HAVCR1, ANXA10, CDCA8, EPO, S100A9, TTK, KLRB1, SPP1, STC2, CYP26B1, GPC1, G6PD, and CBX2. In either dataset, MRS was identified as an independent risk factor for OS in HCC patients. Additionally, our research indicated that a high-risk score in the MRS model was significantly correlated with tumor staging, pathological grade, tumor–node–metastasis (TNM) stage, and survival. Several genes of the human leukocyte antigen (HLA) family and immune checkpoints were highly expressed in the high-risk group. In addition, the frequency of tumor mutations was also higher in the high-risk group. According to our analyses, a higher risk score in the MRS model may predict a better response to immunotherapy.

Total Lesion Glycolysis on 18F-FDG PET/CT Is a Better Prognostic Factor Than Tumor Dose on 90Y PET/CT in Patients With Hepatocellular Carcinoma Treated With 90Y Transarterial Radioembolization.

This study aimed to evaluate the prognostic value of metabolic parameters on 18F-FDG PET/CT and tumor dose (TD) on posttreatment 90Y PET/CT in patients with hepatocellular carcinoma (HCC) who underwent 90Y transarterial radioembolization (TARE). Forty-seven HCC patients treated with 90Y TARE were retrospectively enrolled between January 2013 and October 2018. 18F-FDG PET/CT was performed before treatment. Maximum tumor SUV-to-mean normal liver SUV ratio (TLR), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured for each patient. Voxel dosimetry was performed on 90Y PET/CT images to measure TD. The prognostic significance of metabolic parameters on 18F-FDG PET/CT, TD on 90Y PET/CT, and clinical factors for overall survival (OS) was evaluated. In addition, TD on 90Y PET/CT was analyzed in relation to the administered dose of 90Y-labeled microspheres and metabolic parameters on 18F-FDG PET/CT. The median patient age was 57 years, and 37 patients (78.7%) were men. During the follow-up period, 25 patients (53.2%) died. In univariable analysis, Barcelona Clinic Liver Cancer stage C, Child-Pugh score, TD on 90Y PET/CT, TLR, MTV, and TLG were significant prognostic factors affecting OS (P < 0.05). In multivariable analysis, Barcelona Clinic Liver Cancer stage C and high TLG on 18F-FDG PET/CT were independent prognostic factors for OS (P < 0.05). The 1-year OS rates were 72.9% in patients with low TLG and 33.3% in patients with high TLG (P < 0.05). We also found that TD on 90Y PET/CT was not correlated with the administered dose of 90Y-labeled microspheres, but negatively correlated with TLG on pretreatment 18F-FDG PET/CT (P < 0.05). TLG, a parameter incorporating both the degree of 18F-FDG uptake and amount of metabolically active tumor volume on pretreatment 18F-FDG PET/CT, is a better prognostic factor than TD on 90Y PET/CT for predicting OS in HCC patients treated with 90Y TARE.