Prognostic Biomarker For Hepatocellular Carcinoma Research Articles

Prognostic value and potential molecular mechanism of ITGB superfamily members in hepatocellular carcinoma.

We analyzed the prognostic value and potential molecular mechanisms of the members of integrin β (ITGB)superfamily in hepatocellular carcinoma (HCC) using data from The Cancer Genome Atlas (TCGA), cBioPortal, Gene Expression Profiling Interactive Analysis (GEPIA), Human Protein Atlas (HPA) HPA, Search Tool for the Retrieval of Interacting Genes/Proteins, GeneMANIA, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), TIMER and Gene set enrichment analysis (GSEA) databases. ITGB4/5 mRNA was upregulated in HCC tissues in contrast to the normal liver tissues, whereas ITGB2/3/8 levels were lower in the former. ITGB4 was the most frequently mutated ITGB gene in HCC. Receiver operating characteristic curve (ROC) analysis showed that the expression levels of ITGB2/3/4/5/7/8 had significant diagnostic value in distinguishing HCC tissues from healthy liver tissues, ITGB8 had the highest diagnostic efficacy. The ITGB1/3/6/8 were also upregulated in the HCC tissues in contrast to healthy liver tissues. The expression of ITGB8 was verified by immunohistochemistry (IHC). Furthermore, ITGB6 and ITGB7 expression levels were strongly associated with the overall survival (OS) of HCC patients. The ITGB superfamily members exhibited homology and interactions in protein structure. In addition, ITGB6 together with ITGB7 were negatively related to the infiltration of multiple immune cell populations. GSEA results showed that ITGB6 was enriched in HCC migration and recurrence, whereas ITGB7 was significantly enriched in HIPPO, TOLL and JAK-STAT signaling pathways. In conclusion, ITGB6 and ITGB7 genes are possible to be prognostic biomarkers for HCC.

Novel Long Noncoding RNAs, LINC01093 and MYLK-AS1, Serve as Potential Diagnostic and Prognostic Biomarkers or Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most fatal human malignancies worldwide. In this research, we aimed to identify long noncoding RNAs (lncRNAs) as biomarkers for HCC diagnosis and prognosis. lncRNA expression profiles were obtained from Gene Expression Omnibus and The Cancer Genome Atlas databases. The differentially expressed lncRNAs between HCC and adjacent tissues were analyzed with bioinformatic tools. Four lncRNAs with area under the curve of the receiver operating characteristic curve >0.9 were selected from both datasets. Univariate and Kaplan-Meier analyses were performed to obtain LINC01093, MYLK-AS1, and MCM3AP-AS1 as the optimal diagnostic and prognostic biomarkers. Finally, qPCR confirmed that LINC01093 and MYLK-AS1 were significantly differentially expressed in HCC and adjacent normal tissues. In general, we demonstrated that novel lncRNAs, LINC01093 and MYLK-AS1, could be used as potential diagnostic and prognostic biomarkers for HCC.

The lipid peroxidation-derived DNA adduct γ-OHPdG as a diagnostic and prognostic biomarker in hepatocellular carcinoma.

Chronic inflammation and lipid peroxidation (LPO) are associated with the pathogenesis of hepatocellular carcinoma (HCC), and γ-hydroxy-1, N2-propanodeoxyguanosine (γ-OHPdG) is a promutagenic DNA adduct derived from LPO. This study aimed to examine the relationship between γ-OHPdG and the progression of liver carcinogenesis. Primary HCC specimens were obtained from 228 patients and cirrhosis specimens from 46 patients. The patients were followed up with after surgery via outpatient visits and telephone calls. The levels of γ-OHPdG were determined by immunohistochemical analysis in the carcinomatous tissues together with adjacent and cirrhosis tissues. γ-OHPdG levels in the cancerous tissues were significantly higher compared to adjacent tissues (P < 0.001) and also higher than the ones from the tissues of cirrhosis patients. Along with tumor size, histological grade, MVI grade, T stage, the percentage of ki67-positive cells and HCC progression, γ-OHPdG levels in cancerous tissues showed a gradually increasing trend. Moreover, prognostic analysis showed that higher γ-OHPdG levels in cancerous tissues were strongly correlated with lower overall survival (P < 0.001), lower intrahepatic recurrence-free survival (P < 0.001) and lower distant metastasis-free survival (P < 0.05). There was a trend, although not statistically significant, of increased levels of γ-OHPdG in cirrhosis cases that advanced to HCC, whereas γ-OHPdG levels reversely correlated with the period of time observed for cirrhosis advanced to HCC. These results suggest that γ-OHPdG is a prognostic biomarker for predicting outcomes in HCC, and may serve as a prospective indicator for predicting HCC in cirrhosis patients.

Identification of an immune-related 6-lncRNA panel with a good performance for prognostic prediction in hepatocellular carcinoma by integrated bioinformatics analysis.

Hepatocellular carcinoma (HCC) is one of the most malignant tumors with a poor prognosis. The long non-coding RNA (lncRNA) has been found to have great potential as a prognostic biomarker or therapeutic target for cancer patients. However, the prognostic value and tumor immune infiltration of lncRNAs in HCC has yet to be fully elucidated. To identify prognostic biomarkers of lncRNA in HCC by integrated bioinformatics analysis and explore their functions and relationship with tumor immune infiltration. The prognostic risk assessment model for HCC was constructed by comprehensively using univariate/multivariate Cox regression analysis, Kaplan-Meier survival analysis, and the least absolute shrinkage and selection operator regression analysis. Subsequently, the accuracy, independence, and sensitivity of our model were evaluated, and a nomogram for individual prediction in the clinic was constructed. Tumor immune microenvironment (TIME), immune checkpoints, and human leukocyte antigen alleles were compared in high- and low-risk patients. Finally, the functions of our lncRNA signature were examined using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and gene set enrichment analysis. A 6-lncRNA panel of HCC consisting of RHPN1-AS1, LINC01224, CTD-2510F5.4, RP1-228H13.5, LINC01011, and RP11-324I22.4 was eventually identified, and show good performance in predicting the survivals of patients with HCC and distinguishing the immunomodulation of TIME of high- and low-risk patients. Functional analysis also suggested that this 6-lncRNA panel may play an essential role in promoting tumor progression and immune regulation of TIME. In this study, 6 potential lncRNAs were identified as the prognostic biomarkers in HCC, and the regulatory mechanisms involved in HCC were initially explored.

ZNF765 is a prognostic biomarker of hepatocellular carcinoma associated with cell cycle, immune infiltration, m6A modification, and drug susceptibility.

Hepatocellular carcinoma (HCC) is an ongoing challenge worldwide. Zinc finger protein 765 (ZNF765) is an important zinc finger protein that is related to the permeability of the blood-tumor barrier. However, the role of ZNF765 in HCC is unclear. This study evaluated the expression of ZNF765 in hepatocellular carcinoma and the impact of its expression on patient prognosis based on The Cancer Genome Atlas (TCGA). Immunohistochemical assays (IHC) were used to examine protein expression. Besides, a colony formation assay was used to examine cell viability. We also explored the relationship between ZNF765 and chemokines in the HCCLM3 cells by qRT-PCR. Moreover, we examined the effect of ZNF765 on cell resistance by measurement of the maximum half-inhibitory concentration. Our research revealed that ZNF765 expression in HCC samples was higher than that in normal samples, whose upregulation was not conducive to the prognosis. The results of GO, KEGG, and GSEA showed that ZNF765 was associated with the cell cycle and immune infiltration. Furthermore, we confirmed that the expression of ZNF765 had a strong connection with the infiltration level of various immune cells, such as B cells, CD4+ T cells, macrophages, and neutrophils. In addition, we found that ZNF765 was associated with m6A modification, which may affect the progression of HCC. Finally, drug sensitivity testing found that patients with HCC were sensitive to 20 drugs when they expressed high levels of ZNF765. In conclusion, ZNF765 may be a prognostic biomarker related to cell cycle, immune infiltration, m6A modification, and drug sensitivity for hepatocellular carcinoma.

METTL5 serves as a diagnostic and prognostic biomarker in hepatocellular carcinoma by influencing the immune microenvironment

Despite the abnormal expression of 18S rRNA m6A methyltransferase METTL5 being reported in some types of human malignancies, but its effect on hepatocellular carcinoma (HCC) remains to be unclear. This study aims to elucidate the influences of METTL5 on the carcinogenesis and progression of HCC. Expressions of METTL5 gene, transcript, protein, and promoter methylation in HCC were examined through multiple databases, c-BioPortal was used to confirm the genomic alterations of METTL5, the biological functions, target networks of kinases and microRNAs of METTL5, and its interactive differential genes were investigated through LinkedOmics. The possible correlation of METTL5 with the tumor-related infiltration of immune cells for HCC were explored comprehensively by using the online tools of TIMER and TISIDB. Expressions of METTL5 gene, mRNA, and protein were considerably overexpressed in HCC samples in comparison with healthy samples. The high methylation of the METTL5 promoter was observed in HCC tissues. Elevated METTL5 expression exhibited unfavorable survival outcomes in HCC patients. METTL5 expression were enriched in the signaling pathways of ribosome and oxidative phosphorylation, mismatch repair, and spliceosome through the involvement of several cancer-related kinases and miRNAs. The METTL5 expression has a positive correlation with the infiltration degree of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells in HCC. Marker genes of tumor immune-infiltrated cells have strong connection with METTL5. Furthermore, the upregulation of METTL5 was strongly correlated with the immune regulation of immunomodulators, chemokines, and chemokine receptors in the immune microenvironment. The oncogenesis and development of HCC are closely related to METTL5 expression, and the overexpression of METTL5 resulted in the poor survival outcome of HCC patients by regulating tumor immune microenvironment.

The functions and roles of C2H2 zinc finger proteins in hepatocellular carcinoma.

C2H2 zinc finger (C2H2-ZF) proteins are the majority group of human transcription factors and they have many different molecular functions through different combinations of zinc finger domains. Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors and the main reason for cancer-related deaths worldwide. More and more findings support the abnormal expression of C2H2-ZF protein in the onset and progression of HCC. The C2H2-ZF proteins are involved in various biological functions in HCC, such as EMT, stemness maintenance, metabolic reprogramming, cell proliferation and growth, apoptosis, and genomic integrity. The study of anti-tumor drug resistance also highlights the pivotal roles of C2H2-ZF proteins at the intersection of biological functions (EMT, stemness maintenance, autophagy)and chemoresistance in HCC. The involvement of C2H2-ZF protein found recently in regulating different molecules, signal pathways and pathophysiological activities indicate these proteins as the possible therapeutic targets, and diagnostic or prognostic biomarkers for HCC.

Comprehensive analysis identifies CLEC1B as a potential prognostic biomarker in hepatocellular carcinoma

BackgroundC-type lectin domain family 1 member B (CLEC1B, encoding the CLEC-2 protein), a member of the C-type lectin superfamily, is a type II transmembrane receptor involved in platelet activation, angiogenesis, and immune and inflammatory responses. However, data regarding its function and clinical prognostic value in hepatocellular carcinoma (HCC) remain scarce.MethodsThe expression of CLEC1B was explored using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. RT-qPCR, western blot, and immunohistochemistry assays were employed to validate the downregulation of CLEC1B. Univariate Cox regression and survival analyses were used to evaluate the prognostic value of CLEC1B. Gene Set Enrichment Analysis (GSEA) was conducted to investigate the potential association between cancer hallmarks and CLEC1B expression. The TISIDB database was applied to search for the correlation between immune cell infiltration levels and CLEC1B expression. The association between CLEC1B and immunomodulators was conducted by Spearman correlation analysis based on the Sangerbox platform. Annexin V-FITC/PI apoptosis kit was used for the detection of cell apoptosis.ResultsThe expression of CLEC1B was low in various tumors and exhibited a promising clinical prognostic value for HCC patients. The expression level of CLEC1B was tightly associated with the infiltration of various immune cells in the HCC tumor microenvironment (TME) and positively correlated with a bulk of immunomodulators. In addition, CLEC1B and its related genes or interacting proteins are implicated in multiple immune-related processes and signaling pathways. Moreover, overexpression of CLEC1B significantly influenced the treatment effects of sorafenib on HCC cells.ConclusionsOur results reveal that CLEC1B could serve as a potential prognostic biomarker and may be a novel immunoregulator for HCC. However, its function in immune regulation should be further explored.

TMEM147 Correlates with Immune Infiltration and Serve as a Potential Prognostic Biomarker in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies and is associated with high mortality. Transmembrane protein 147 (TMEM147) is a seven-transmembrane protein that may mediate immune regulation. However, the relevance of TMEM147 to immune regulation in HCC and the prognosis of HCC patients are unclear. We analyzed TMEM147 expression in HCC by using the Wilcoxon rank-sum test. Real time quantitative PCR (RT-qPCR) and Western blot analysis of tumor tissues and cell lines were used to verify TMEM147 expression in HCC. The influence of TMEM147 on HCC prognosis was assessed using Kaplan-Meier analysis, Cox regression analysis, and a prognostic nomogram. The functions of the TMEM147-related differentially expressed genes (DEGs) were identified by Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses and gene set enrichment analysis (GSEA). In addition, we examined the associations between TMEM147 expression and immune infiltration using single-sample gene set enrichment analysis (ssGSEA) and immunofluorescence staining of HCC tissues. Our results showed that the expression of TMEM147 was significantly higher in human HCC tissues than in adjacent normal liver tissues, with similar findings in human HCC cell lines. High TMEM147 expression was correlated with T stage, pathological stage, histological grade, race, alpha-fetoprotein level, and vascular invasion in HCC. Moreover, we revealed that high TMEM147 expression was associated with shorter survival times and that TMEM147 could be a risk factor for overall survival, along with T stage, M stage, pathological stage, and tumor status. Mechanistic studies revealed that high TMEM147 expression was linked to the B lymphocyte, antigen response, IL6 signaling pathway, cell cycle, Kirsten rat sarcoma viral oncogene homolog (KRAS) signaling pathway, and myelocytomatosis oncogene (MYC) targets. Correspondingly, TMEM147 expression was positively associated with the infiltration of immune cells, including Th2 cells, follicular helper T cells, macrophages, and NK CD56 bright cells in HCC. TMEM147 might be a biomarker for poor prognosis and is related to immune cell infiltration in HCC.

Tumor suppressor CLCA1 inhibits angiogenesis via TGFB1/SMAD/VEGF cascade and sensitizes hepatocellular carcinoma cells to Sorafenib

BackgroundHepatocellular carcinoma (HCC) is a highly vascularized tumor with a poor prognosis. Novel vascular-related therapeutic targets and prognostic markers remain urgently needed. AimsTo investigate the role and mechanism of CLCA1 in hepatocellular carcinoma. MethodsImmunofluorescence, Co-immunoprecipitation and rescue experiment were used to determine the specific mechanisms of CLCA1. Chemosensitivity assay was used to measure the impact of CLCA1 on Sorafenib. ResultsCLCA1 was dramatically downregulated in hepatocellular carcinoma cell lines and tissues. Ectopic expression of CLCA1 induced cell apoptosis and G0/G1 phase arrest while suppressed cell growth, inhibited migration and invasion, reversal of epithelial mesenchymal transition in vitro and reduced xenograft tumor growth in vivo. Mechanistically, CLCA1 could co-localize and interact with TGFB1, thereby suppressing HCC angiogenesis through the TGFB1/SMAD/VEGF signaling cascade in vitro and in vivo. Moreover, CLCA1 also enhanced the sensitivity of HCC cells to the first-line targeted therapy, Sorafenib. ConclusionCLCA1 sensitizes HCC cells to Sorafenib and suppresses hepatocellular carcinoma angiogenesis through downregulating TGFB1 signaling cascade. This newly identified CLCA1 signaling pathway may help guide the anti-angiogenesis therapies for hepatocellular carcinoma. We also support the possibility of CLCA1 being a prognostic biomarker for hepatocellular carcinoma.

CD69 serves as a potential diagnostic and prognostic biomarker for hepatocellular carcinoma

The prevalence and mortality of hepatocellular carcinoma (HCC) are still increasing. This study aimed to identify potential therapeutic targets related to patient prognosis. Data were downloaded from TCGA, GSE25097, GSE36376, and GSE76427 datasets. Differential analysis and enrichment analysis were performed in HCC. Cell deaths were evaluated, and least absolute shrinkage and selection operator regression (LASSO) regression was analyzed to screen candidate genes. Additionally, immune cell infiltration in HCC was assessed. We identified 4088 common DEGs with the same direction of differential expression in all four datasets, they were mainly enriched in immunoinflammation and cell cycle pathways. Apoptosis was significantly suppressed in HCC in GSEA and GSVA. After LASSO regression analysis, we screened CD69, CDC25B, MGMT, TOP2A, and TXNIP as candidate genes. Among them, CD69 significantly influenced the overall survival of HCC patients in both TCGA and GSE76427. CD69 may be a protective factor for outcome of HCC patients. In addition, CD69 was positive correlation with T cells and CD3E. CD69, CDC25B, MGMT, TOP2A, and TXNIP were potential diagnostic and prognostic target for HCC, especially CD69.

MARCKS is a New Prognostic Biomarker in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common type of cancers, but there is still a lack of known biomarkers for the effective diagnosis or prognosis of HCC. Myristoylated alanine-rich C-kinase substrate (MARCKS) is a substrate of protein kinase C, which was located in the cell plasma membrane. The purpose of our study was to evaluate the role of MARCKS in HCC. The role of MARCKS in HCC was explored by bioinformatics and experiment. We demonstrated that MARCKS expression was significantly elevated in HCC datasets of TCGA. MARCKS was up-regulated in tumor sample in HCC. Functional enrichment indicated that MARCKS-related differentially expressed genes (DEGs) were mainly enriched in cell junction tissue, response to growth factors and cell population proliferation. Tumor and ECM-receptor interactions related pathways were enriched by the KEGG. MARCKS expression in HCC patients was higher in females, younger individuals, and those at worse clinical stages. Cox regression analysis showed that MARCKS expression was a risk factor for overall survival and disease-specific survival of patients. MARCKS was up-regulated in HCC, may play a crucial role in HCCs, and has prognostic value for clinical outcomes.

LOXL2 serves as a prognostic biomarker for hepatocellular carcinoma by mediating immune infiltration and vasculogenic mimicry.

The development of human hepatocellular carcinoma (HCC) is a multistep process that is accompanied by progressive changes in the liver microenvironment, including immune evasion and angiogenesis. Lysyl oxidase-like 2 (LOXL2) has been suggested to contribute to tumour progression and metastasis; however, the underlying mechanism remains unclear. The purpose of the present study was to explore the relationship between LOXL2 and immune infiltration and vasculogenic mimicry (VM) and to identify the role of LOXL2 in HCC diagnosis prognosis evaluation. The Cancer Genome Atlas (TCGA), UALCAN, GEPIA and Kaplan-Meier plotter databases were used to analyse LOXL2 expression and perform survival analysis. The Tumour Immune Estimation Resource (TIMER) was used to analyse immune cell infiltration, immune cell biomarkers and immune checkpoints. Immunohistochemistry (IHC) of 201 HCC samples was used to confirm the expression of LOXL2 and its relationship with VM. Coimmunoprecipitation (co-IP) and gain- and loss-of-function studies were performed to confirm the molecular mechanism of LOXL2 in VM. The expression of LOXL2 in HCC was higher than that in normal tissues at both the mRNA and protein levels. High expression of LOXL2 was associated with a poorer prognosis of HCC. The genetic alteration rate of LOXL2 was 5%. LOXL2 was positively related to immune cell infiltration and immune checkpoints (PD-1 and CTLA-4) in HCC. Co-IP showed that LOXL2 can interact directly with IQGAP1. Both gain- and loss-of-function studies showed that LOXL2 significantly induced cell migration, invasion and VM formation when IQGAP1 was upregulated. LOXL2 is involved in immune cell infiltration and promotes VM by upregulating IQGAP1. LOXL2 can be used as a novel biomarker for HCC diagnosis and prognosis prediction.

NIFK, an independent prognostic biomarker of hepatocellular carcinoma, is correlated with immune infiltration

BackgroundThe molecular mechanisms that lead to hepatocellular carcinoma (HCC), a highly common malignant tumor, are currently unclear. In fact, while the nucleolar protein that interacts with the FHA domain of pKi-67 (NIFK) is known to promote lung cancer progression, its specific role in HCC remains unknown. ResultsIn HCC tissues, NIFK was significantly overexpressed in comparison with normal tissues. In The Cancer Genome Atlas (TCGA) database, NIFK expression showed a good prediction value according to an ROC curve and it was linked to poor progression-free interval, disease-specific survival and overall survival. Furthermore, the level of NIFK expression in HCC was significantly correlated with tumor stage, AFP (ng/mL), OS event, DSS event and PFI event. Based on GSEA evaluations, differentially expressed NIFK genes exhibited enrichment for fatty acid metabolism, oxidative phosphorylation as well as cancer, cell cycle, MAPK, TGF, WNT and NOTCH signaling pathways. The TIMER database analysis further revealed positive associations between NIFK expression and the immune cells, such as dendritic cells, neutrophils, macrophages, CD4+ T cells, CD8+ T cells and B cells. Also, the NIFK expression was positively correlated with immune checkpoints (PD1/PD-L1 and CTLA4). The experimental verification determined that NIFK knockdown could thwart HCC cellular properties of proliferation, metastasis and invasiveness. Univariate and multivariate Cox hazard regression validated NIFK expression as an independent prognostic marker in HCC. ConclusionsNIFK has theragnostic potential as a separate prognostic factor or novel biomarker involved in the immune infiltration of HCC.How to cite: Cheng F, Yuan L, Wu Z, et al. NIFK, an independent prognostic biomarker of hepatocellular carcinoma, is correlated with immune infiltration. Electron J Biotechnol 2023;63. https://doi.org/10.1016/j.ejbt.2023.01.003.

Identification of therapeutic targets and prognostic biomarkers among CXC chemokines in hepatocellular carcinoma microenvironment.

Hepatocellular carcinoma (HCC) is characterized by occult onset, rapid progression and poor prognosis. CXC chemokines play an important role in tumor microenvironment and development. The potential mechanistic values of CXC chemokines as clinical biomarkers and therapeutic targets in HCC have not been fully clarified. ONCOMINE, UALCAN, GEPIA, cBioPortal, SurvExpress, MethSurv, SurvivalMeth, String, GeneMANIA, DAVID, Metascape, TRRUST, LinkedOmics, and Timer were applied in this study. The transcriptional levels of CXCL9/16/17 in HCC tissues were significantly elevated while CXCL1/2/5/6/7/12/14 were significantly reduced. significant correlation was found between the expression of CXC3/5 and the pathological stage of HCC patients. High level of CXCL4 was associated with a longer disease-free survival. For overall survival, lower expressions of CXCL1/3/5/8 and higher expressions of CXCL2 were associated with a better outcome. In addition, the prognostic values of CXC chemokines signature in HCC were explored in four independent cohorts, the high-risk group displayed unfavorable survival outcome compared with the low-risk group. And for the prognostic value of the DNA methylation of CXC chemokines, we identified the CpGs which were significantly associated with prognosis in HCC patients. DNA methylation signature analysis also showed a statistically significant association between the high- and low-risk group. For potential mechanism, the neighbor gene networks, interaction analyses, functional enrichment analyses of CC chemokine receptors in HCC were performed, the transcription factor targets, kinase targets, and miRNA targets of CXC chemokines were also identified in HCC. We also found significant correlations among CXC chemokines expression and the infiltration of immune cells, the tumor infiltration levels among HCC with different somatic copy number alterations of these chemokine receptors were also assessed. Moreover, the Cox proportional hazard model showed that CCR2/6/8/12, B_cell, macrophage and dendritic _cell were significantly related to the clinical outcome of HCC patients. CXC chemokines might serve as therapeutic targets and prognostic biomarkers in HCC.

Biological function analysis of ARHGAP39 as an independent prognostic biomarker in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common subtype of liver cancer, with a high morbidity and low survival rate. Rho GTPase activating protein 39 (ARHGAP39) is a crucial activating protein of Rho GTPases, a novel target in cancer therapy, and it was identified as a hub gene for gastric cancer. However, the expression and role of ARHGAP39 in hepatocellular carcinoma remain unclear. Accordingly, the cancer genome atlas (TCGA) data were used to analyze the expression and clinical value of ARHGAP39 in hepatocellular carcinoma. Further, the LinkedOmics tool suggested functional enrichment pathways for ARHGAP39. To investigate in depth the possible role of ARHGAP39 on immune infiltration, we analyzed the relationship between ARHGAP39 and chemokines in HCCLM3 cells. Finally, the GSCA website was used to explore drug resistance in patients with high ARHGAP39 expression. Studies have shown that ARHGAP39 is highly expressed in hepatocellular carcinoma and relevant to clinicopathological features. In addition, the overexpression of ARHGAP39 leads to a poor prognosis. Besides, co-expressed genes and enrichment analysis showed a correlation with the cell cycle. Notably, ARHGAP39 may worsen the survival of hepatocellular carcinoma patients by increasing the level of immune infiltration through chemokines. Moreover, N6-methyladenosine (m6A) modification-related factors and drug sensitivity were also found to be associated with ARHGAP39. In brief, ARHGAP39 is a promising prognostic factor for hepatocellular carcinoma patients that is closely related to cell cycle, immune infiltration, m6A modification, and drug resistance.

FARSB serves as a novel hypomethylated and immune cell infiltration related prognostic biomarker in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a prevalent tumor with high morbidity, and an unfavourable prognosis. FARSB is an aminoacyl tRNA synthase, and plays a key role in protein synthesis in cells. Furthermore, previous reports have indicated that FARSB is overexpressed in gastric tumor tissues and is associated with a poor prognosis and tumorigenesis. However, the function of FARSB in HCC has not been studied. The results showed that FARSB mRNA and protein levels were upregulated in HCC and were closely related to many clinicopathological characteristics. Besides, according to multivariate Cox analysis, high FARSB expression was linked with a shorter survival time in HCC and may be an independent prognostic factor. In addition, the FARSB promoter methylation level was negatively associated with the expression of FARSB. Furthermore, enrichment analysis showed that FARSB was related to the cell cycle. And TIMER analysis revealed that the FARSB expression was closely linked to tumor purity and immune cell infiltration. The TCGA and ICGC data analysis suggested that FARSB expression is greatly related to m6A modifier related genes. Potential FARSB-related ceRNA regulatory networks were also constructed. What's more, based on the FARSB-protein interaction network, molecular docking models of FARSB and RPLP1 were constructed. Finally, drug susceptibility testing revealed that FARSB was susceptible to 38 different drugs or small molecules. FARSB can serve as a prognostic biomarker for HCC and provide clues about immune infiltration, and m6A modification.

Nucleoporin 107 is a prognostic biomarker in hepatocellular carcinoma associated with immune infiltration.

To assess the diagnostic value and clinical significance of nucleoporin 107 (NUP107) in hepatocellular carcinoma (HCC), and explore the possible mechanisms. The transcriptomic and clinical data of HCC patients were retrieved from The Cancer Genome Atlas (TCGA) and GEO databases. Tissue specimens were collected from HCC patients in the Guangxi area. According to the expression levels and prognostic characteristics of NUP107, ROC curves and nomogram models were constructed using the R package. NUP107 was highly expressed in 26 human cancers including HCC, and was associated with advanced HCC staging and worse prognosis. NUP107 showed satisfactory ability to predict the prognosis of HCC patients (AUC >0.8). Results of gene set enrichment analysis (GSEA) further showed that NUP107 was mainly associated with cell cycle-related pathways such as the cell cycle, DNA replication, G2M checkpoint, E2F target, and mitotic spindle. In addition, NUP107 was also associated with immune infiltration in HCC and showed significant positive correlation with immune checkpoints (PD-L1 and TIM-3).

CircFOXK2 promotes hepatocellular carcinoma progression and leads to a poor clinical prognosis via regulating the Warburg effect

BackgroundThe Warburg effect is well-established to be essential for tumor progression and accounts for the poor clinical outcomes of hepatocellular carcinoma (HCC) patients. An increasing body of literature suggests that circular RNAs (circRNAs) are important regulators for HCC. However, few circRNAs involved in the Warburg effect of HCC have hitherto been investigated. Herein, we aimed to explore the contribution of circFOXK2 to glucose metabolism reprogramming in HCC.MethodsIn the present study, different primers were designed to identify 14 circRNAs originating from the FOXK2 gene, and their differential expression between HCC and adjacent liver tissues was screened. Ultimately, circFOXK2 (hsa_circ_0000817) was selected for further research. Next, the clinical significance of circFOXK2 was evaluated. We then assessed the pro-oncogenic activity of circFOXK2 and its impact on the Warburg effect in both HCC cell lines and animal xenografts. Finally, the molecular mechanisms of how circFOXK2 regulates the Warburg effect of HCC were explored.ResultsCircFOXK2 was aberrantly upregulated in HCC tissues and positively correlated with poor clinical outcomes in patients that underwent radical hepatectomy. Silencing of circFOXK2 significantly suppressed HCC progression both in vitro and in vivo. Mechanistically, circFOXK2 upregulated the expression of protein FOXK2-142aa to promote LDHA phosphorylation and led to mitochondrial fission by regulating the miR-484/Fis1 pathway, ultimately activating the Warburg effect in HCC.ConclusionsCircFOXK2 is a prognostic biomarker of HCC that promotes the Warburg effect by promoting the expression of proteins and miRNA sponges that lead to tumor progression. Overall, circFOXK2 has huge prospects as a potential therapeutic target for patients with HCC.

SEPT9 Expression in Hepatic Nodules: An Immunohistochemical Study of Hepatocellular Neoplasm and Metastasis.

The methylated SEPT9 DNA ( mSEPT9 ) in plasma is a US Food and Drug Administration (FDA)-approved screening biomarker in colorectal cancer and is emerging as a promising diagnostic and prognostic biomarker in hepatocellular carcinoma (HCC). We evaluated the SEPT9 protein expression by immunohistochemistry (IHC) in various hepatic tumors from 164 hepatectomies and explants. Cases diagnosed as HCC (n=68), hepatocellular adenoma (n=31), dysplastic nodule (n=24), and metastasis (n=41) were retrieved. SEPT9 stain was performed on representative tissue blocks showing tumor/liver interface. For HCC, archived IHC (SATB2, CK19, CDX2, CK20, and CDH17) slides were also reviewed. The findings were correlated with demographics, risk factors, tumor size, alpha fetoprotein levels at diagnosis, T stage and oncologic outcomes, with significance defined as P <0.05. Percentage of SEPT9 positivity differed significantly among hepatocellular adenoma (3%), dysplastic nodule (0%), HCC (32%), and metastasis (83%, P <0.001). Compared with patients with SEPT9- HCC, those with SEPT9+ HCC were older (70 vs. 63y, P =0.01). The extent of SEPT9 staining correlated with age ( rs =0.31, P =0.01), tumor grade ( rs =0.30, P =0.01), and extent of SATB2 staining ( rs =0.28, P =0.02). No associations were found between SEPT9 staining and tumor size, T stage, risk factors, CK19, CDX2, CK20, or CDH17 expression, alpha fetoprotein levels at diagnosis, METAVIR fibrosis stage, and oncologic outcome in the HCC cohort. SEPT9 is likely implicated in liver carcinogenesis in a HCC subset. Similar to mSEPT9 DNA measurement in liquid biopsies, SEPT9 staining by IHC may prove helpful as an adjunct diagnostic biomarker with potential prognostic ramifications.