Prognostic Value and Immunological Role of KIFC1 in Hepatocellular Carcinoma
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ABSTRACT:
SUBMITTER: Li D
PROVIDER: S-EPMC8802309 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe protein-coding gene RAB22A, a member of the RAS oncogene family, is amplified or overexpressed in certain cancers. However, its action mechanism in hepatocellular carcinoma (HCC) remains unclear. Here, we aimed to examine the connection between RAB22A and survival prognosis in HCC and explore the biological significance of RAB22A.MethodsA database-based pan-cancer expression analysis of RAB22A was performed. Kaplan-Meier analysis and Cox regression were performed to evaluate the association between RAB22A expression and survival prognosis in HCC. Using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA), various potential biological functions and regulatory pathways of RAB22A in HCC were discovered. Tumor immune infiltration was studied using the single sample gene set enrichment analysis (ssGSEA) method. N6-methyladenosine modifications and the regulatory network of competitive endogenous RNA (ceRNA) were verified in the TCGA cohort.ResultsRAB22A was upregulated in HCC samples and cell lines. A high RAB22A expression in HCC was strongly correlated with sex, race, age, weight, TNM stage, pathological stage, tumor status, histologic grade, TP53 mutation status, and alpha fetal protein (AFP) levels. Overexpression of RAB22A indicated a poor prognosis was related to overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI). GO and KEGG analyses revealed that the differentially expressed genes related to RAB22A might be involved in the proteasomal protein catabolic process, ncRNA processing, ribosome ribosomal subunit, protein serine/threonine kinase activity, protein serine kinase activity, Endocytosis, and non-alcoholic fatty liver disease. GSEA analyses revealed that the differentially expressed genes related to RAB22A might be involved in the T cell receptor, a co-translational protein, that binds to the membrane, axon guidance, ribosome, phagocytosis, and Eukaryotic translation initiation. RAB22A was correlated with N6-methyladenosine expression in HCC and established RAB22A-related ceRNA regulatory networks. Finally,RAB22A expression was positively connected the levels of infiltrating with T helper cells, Tcm cells, and Th2 cells,In contrast, we observed negatively correlations with cytotoxic cells, DCs, and pDCs cells.Moreover,RAB22A expression showed a strong correlation with various immunomarkergroups in HCC.ConclusionsRAB22A is a potential therapeutic target for improving HCC prognosis and is closely related to immune cell infiltration.
| S-EPMC10021109 | biostudies-literature
Project description:BackgroundHepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. Long non-coding RNAs (lncRNAs) play important roles in the occurrence and development of HCC through multiple pathways. Our previous study reported the specific molecular mechanism for sulfatide regulation of integrin αV expression and cell adhesion in HCC cells through lncRNA AY927503. Next, it is necessary to identify more sulfatide-related lncRNAs, explore their clinical signifcance, and determine new targeted treatment strategies.MethodsMicroarrays were used to screen a complete set of lncRNAs with different expression profiles in sulfatide-treated cells. Sulfatide-related lncRNAs expression data and corresponding HCC patient survival information were obtained from the The Cancer Genome Atlas (TCGA) database, and the prognosis prediction model was constructed based on Cox regression analysis. Methylated RNA immunoprecipitation with next generation sequencing (MeRIP-seq) was used to detemine the effect of sulfatide on lncRNAs m6A modification. Tumor Immune Estimation Resource (TIMER) and Gene set nnrichment analysis (GSEA) were utilized to enrich the immune and functional pathways of sulfatide-related lncRNAs.ResultsA total of 85 differentially expressed lncRNAs (|Fold Change (FC)|>2, P<0.05) were screened in sulfatide-treated HCC cells. As a result, 24 sulfatide-related lncRNAs were highly expressed in HCC tissues, six of which were associated with poor prognosis in HCC patients. Based on thses data, a sulfatide-related lncRNAs prognosis assessment model for HCC was constructed. According to this risk score analysis, the overall survival (OS) curve showed that the OS of high-risk patients was significantly lower than that of low-risk patients (P<0.05). Notably, the expression difference in sulfatide-related lncRNA NRSN2-AS1 may be related to sulfatide-induced RNA m6A methylation. In addition, the expression level of NRSN2-AS1 was significantly positively correlated with immune cell infiltration in HCC and participated in the peroxisome and Peroxisome proliferator-activated receptor (PPAR) signaling pathways.ConclusionsIn conclusion, sulfatide-related lncRNAs might be promising prognostic and therapeutic targets for HCC.
| S-EPMC9929346 | biostudies-literature
Project description:Background: Liver cancer stem cells, characterized by self-renewal and initiating cancer cells, were decisive drivers of progression and therapeutic resistance in hepatocellular carcinoma (HCC). However, a comprehensive understanding of HCC stemness has not been identified. Methods: RNA sequencing information, corresponding clinical annotation, and mutation data of HCC were downloaded from The Cancer Genome Atlas-LIHC project. Two stemness indices, mRNA expression-based stemness index (mRNAsi) and epigenetically regulated-mRNAsi, were used to comprehensively analyze HCC stemness. Estimation of Stromal and Immune Cells in Malignant Tumors using Expression Data and single-sample gene-set enrichment analysis algorithm were performed to characterize the context of tumor immune microenvironment (TIME). Next, differentially expressed gene (DEG) analysis and weighted gene co-expression network analysis (WGCNA) were employed to identify significant mRNAsi-related modules with hub genes. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment pathways were analyzed to functionally annotate these key genes. The least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed to establish a prognostic signature. Kaplan-Meier survival curves and receiver operating characteristic (ROC) analysis were applied for prognostic value validation. Seven algorithms (XCELL, TIMER, QUANTISEQ, MCPcounter, EPIC, CIBERSORT, and CIBERSORT-ABS) were utilized to draw the landscape of TIME. Finally, the mutation data were analyzed by employing "maftools" package. Results: mRNAsi was significantly elevated in HCC samples. mRNAsi escalated as tumor grade increased, with poor prognosis presenting the higher stemness index. The stemness-related (greenyellow) modules with 175 hub genes were screened based on DEGs and WGCNA. A prognostic signature was established using LASSO analysis of prognostic hub genes to classify samples into two risk subgroups, which exhibited good prognostic performance. Additionally, prognostic risk-clinical nomogram was drawn to estimate risk quantitatively. Moreover, risk score was significantly associated with contexture of TIME and immunotherapeutic targets. Finally, potential interaction between risk score with tumor mutation burden (TMB) was elucidated. Conclusion: This work comprehensively elucidated that stemness characteristics served as a crucial player in clinical outcome, complexity of TIME, and immunotherapeutic prediction from both mRNAsi and mRNA level. Quantitative identification of stemness characteristics in individual tumor will contribute into predicting clinical outcome, mapping landscape of TIME further optimizing precision immunotherapy.
| S-EPMC8365341 | biostudies-literature
Project description:Scavenger receptor class F member 1 (SCARF1) is thought to play an important role in the selective recruitment of CD4+ T cells to liver sinusoidal endothelial cells during chronic liver disease. However, the contribution of SCARF1 to hepatocellular carcinoma (HCC) is currently unknown. We utilized publically-available RNA-sequencing data from The Cancer Genome Atlas (TGCA) to explore SCARF1 expression in HCC and correlated it with a number of clinicopathological features. Flow adhesion assays were used to determine the role of SCARF1 in CD4+ T cell subset recruitment. SCARF1 expression was downregulated in HCC tumor tissues, compared to non-tumoral tissues, and loss of SCARF1 expression was associated with poorly differentiated/aggressive tumors. Additionally, higher SCARF1 expression in HCC tumor tissues was highly prognostic of better overall, disease-free and progression-free survival. SCARF1 within HCC was largely associated with tumor endothelial cells and adhesion studies suggested that it played a role in the specific recruitment of proinflammatory CD4+ T cells (CD4+CD25-) to HCC tumor tissues. Endothelial SCARF1 expression in tumor biopsies may provide critical prognostic information. Additionally, SCARF1 may also be a novel endothelial target that could help re-programme the microenvironment of HCC by promoting effector T cell tumor infiltration.
| S-EPMC8336907 | biostudies-literature
Project description:The transcription factor BarH-like homeobox 2 (BARX2), a member of the Bar-like homeobox gene family, is involved in cell proliferation, differentiation, immune responses and tumorigenesis. However, the potential role of BARX2 in the development of liver hepatocellular carcinoma (LIHC) remains unclear. Therefore, we aimed to study the biological role of BARX2 in hepatocellular carcinoma. Through the UALCAN, GTEx PORTAL, TIMER 2.0, LinkedOmics, SMART, MethSurv, Metascape, GSEA and STRING public databases, the BARX2 mRNA level, prognostic value, coexpressed genes, associated differentially expressed genes, DNA methylation and functional enrichment of LIHC patients were studied. The relationships between BARX2 expression and various clinical or genetic parameters of LIHC patients were determined using data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and BEAT LIHC databases. In addition, the biological function of BARX2 in LIHC was studied in vitro. Through large-scale data mining, our study showed that BARX2 was differentially expressed between different normal and tumour tissues.BARX2 expression in LIHC tissues was significantly lower than that in corresponding controls, especially in patients with T2-4 stage disease. In patients with LIHC, overexpression of BARX2 was an independent poor prognostic factor associated with poor cytogenetic risk and gene mutations. Genomic hypermethylation of the BARX2 gene was associated with upregulated BARX2 expression and poor overall survival (OS) in LIHC. Functional enrichment analysis showed that BARX2 had an immunomodulatory role and was involved in the inflammatory response in LIHC occurrence. In conclusion, the oncogene BARX2 may serve as a new biomarker and prognostic factor for patients with LIHC. The immunomodulatory function of BARX2 deserves further validation in LIHC.
| S-EPMC10170086 | biostudies-literature
Project description:Liver hepatocellular carcinoma (LIHC) remains one of the most common causes of cancer death. Prior research suggested that the PPM1G gene is involved in LIHC. To explore the role of PPM1G in LIHC, we used several online databases. Expression profiling was performed via the Gene Expression Profiling Interactive Analysis (GEPIA), Hepatocellular Carcinoma Database (HCCDB), Oncomine and Human Protein Atlas (HPA) platforms. Mutation profiles were investigated via cBio Cancer Genomics Portal (cBioPortal). Survival analysis was performed via the Kaplan-Meier (KM) plotter and International Cancer Genome Consortium (ICGC) platforms. The biological function of PPM1G was analyzed via the Enrichr database. The influence of PPM1G expression in the tumor immune microenvironment was assessed via Tumor Immune Estimation Resource (TIMER). PPM1G expression was upregulated in various tumors, including LIHC. Overexpression of PPM1G was associated with poor prognosis in LIHC. PPM1G expression might be regulated by promoter methylation, copy number variations (CNVs) and kinases and correlate with immune infiltration. The gene ontology (GO) terms associated with high PPM1G expression were mRNA splicing and the cell cycle. The results suggest that PPM1G is correlated with the prognosis of LIHC patients and associated with the tumor immune microenvironment in LIHC.
| S-EPMC8148464 | biostudies-literature
Project description:BackgroundThis study investigated the prognostic and immunological significance of alpha-L-fucosidase 2 (FUCA2) in hepatocellular cancer (HCC).MethodsThe expression of FUCA2 and its clinical and prognostic values were explored across several databases, namely the University of Alabama Cancer Database, The Cancer Genome Atlas, Gene Expression Profiling Interactive Analysis, and the Human Protein Atlas. The prognostic relevance of FUCA2 was investigated using Kaplan-Meier curves, nomograms, and Cox analysis. The "limma" package in R was used to identify differentially expressed genes between high and low FUCA2 expression. A protein interaction network was established using the Search Tool for the Retrieval of Interacting Genes (STRING), whereas hub genes and clustering modules were identified using Cytoscape. "clusterProfiler", an R package, was used to examine the potential function of FUCA2. Using gene set enrichment analysis, signaling pathways associated with FUCA2 expression were identified. Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT), Tumor Immune Estimation Resource (TIMER) 2.0, and Tumor and Immune System Interaction Database (TISIDB) were used to examine immune infiltration and FUCA2 in HCC.ResultsMany datasets indicated that FUCA2 expression is higher in HCC, and that this is related to age and overall survival (OS). With the cutoff value of 50% as the dividing threshold, the patients were divided into a high-FUCA2 expression group (n=167) and a low-FUCA2 expression group (n=168). High levels of FUCA2 expression coincided with decreased OS. FUCA2 expression in HCC was associated with immune infiltrates. The functional mechanisms of FUCA2 depend on signal release, extracellular matrix collagen, and neuroactive ligands and receptors.ConclusionsIn HCC, increased FUCA2 expression is associated with a poor prognosis and immune infiltration. FUCA2 may serve as an immunological and predictive biomarker for HCC.
| S-EPMC10007884 | biostudies-literature
Project description:BackgroundHepatocellular carcinoma (HCC) ranks the sixth prevalent tumors with high mortality globally. Alternative splicing (AS) drives protein diversity, the imbalance of which might act an important factor in tumorigenesis. This study aimed to construct of AS-based prognostic signature and elucidate the role in tumor immune microenvironment (TIME) and immunotherapy in HCC.MethodsUnivariate Cox regression analysis was performed to determine the prognosis-related AS events and gene set enrichment analysis (GSEA) was employed for functional annotation, followed by the development of prognostic signatures using univariate Cox, LASSO and multivariate Cox regression. K-M survival analysis, proportional hazards model, and ROC curves were conducted to validate prognostic value. ESTIMATE R package, ssGSEA algorithm and CIBERSORT method and TIMER database exploration were performed to uncover the context of TIME in HCC. Quantitative real-time polymerase chain reaction was implemented to detect ZDHHC16 mRNA expression. Cytoscape software 3.8.0 were employed to visualize AS-splicing factors (SFs) regulatory networks.ResultsA total of 3294 AS events associated with survival of HCC patients were screened. Based on splicing subtypes, eight AS prognostic signature with robust prognostic predictive accuracy were constructed. Furthermore, quantitative prognostic nomogram was developed and exhibited robust validity in prognostic prediction. Besides, the consolidated signature was significantly correlated with TIME diversity and ICB-related genes. ZDHHC16 presented promising prospect as prognostic factor in HCC. Finally, the splicing regulatory network uncovered the potential functions of splicing factors (SFs).ConclusionHerein, exploration of AS patterns may provide novel and robust indicators (i.e., risk signature, prognostic nomogram, etc.,) for prognostic prediction of HCC. The AS-SF networks could open up new approach for investigation of potential regulatory mechanisms. And pivotal players of AS events in context of TIME and immunotherapy efficiency were revealed, contributing to clinical decision-making and personalized prognosis monitoring of HCC.
| S-EPMC8017877 | biostudies-literature
Project description:Background: Hepatocellular carcinoma (HCC) is a tumor with high morbidity and high mortality worldwide. DNA methylation, one of the most common epigenetic changes, might serve a vital regulatory role in cancer. Methods: To identify categories based on DNA methylation data, consensus clustering was employed. The risk signature was yielded by systematic bioinformatics analyses based on the remarkably methylated CpG sites of cluster 1. Kaplan-Meier analysis, variable regression analysis, and ROC curve analysis were further conducted to validate the prognosis predictive ability of risk signature. Gene set enrichment analysis (GSEA) was performed for functional annotation. To uncover the context of tumor immune microenvironment (TIME) of HCC, we employed the ssGSEA algorithm and CIBERSORT method and performed TIMER database exploration and single-cell RNA sequencing analysis. Additionally, quantitative real-time polymerase chain reaction was employed to determine the LRRC41 expression and preliminarily explore the latent role of LRRC41 in prognostic prediction. Finally, mutation data were analyzed by employing the "maftools" package to delineate the tumor mutation burden (TMB). Results: HCC samples were assigned into seven subtypes with different overall survival and methylation levels based on 5'-cytosine-phosphate-guanine-3' (CpG) sites. The risk prognostic signature including two candidate genes (LRRC41 and KIAA1429) exhibited robust prognostic predictive accuracy, which was validated in the external testing cohort. Then, the risk score was significantly correlated with the TIME and immune checkpoint blockade (ICB)-related genes. Besides, a prognostic nomogram based on the risk score and clinical stage presented powerful prognostic ability. Additionally, LRRC41 with prognostic value was corroborated to be closely associated with TIME characterization in both expression and methylation levels. Subsequently, the correlation regulatory network uncovered the potential targets of LRRC41 and KIAA1429. Finally, the methylation level of KIAA1429 was correlated with gene mutation status. Conclusion: In summary, this is the first to identify HCC samples into distinct clusters according to DNA methylation and yield the CpG-based prognostic signature and quantitative nomogram to precisely predict prognosis. And the pivotal player of DNA methylation of genes in the TIME and TMB status was explored, contributing to clinical decision-making and personalized prognosis monitoring of HCC.
| S-EPMC8187884 | biostudies-literature
Project description:BackgroundThe immunological inflammatory biomarkers for advanced hepatocellular carcinoma are unclear. We aimed to investigate the association of immunity and inflammatory status with treatment outcomes in patients with advanced hepatocellular carcinoma who received molecular-targeted agents as primary treatment.Patients and methodsWe enrolled 728 consecutive patients with advanced hepatocellular carcinoma who received sorafenib (n = 554) or lenvatinib (n = 174) as primary treatment in Japan between May 2009 and June 2020. Changes in the neutrophil-to-lymphocyte ratio before and 1 month after treatment and their impact on survival were evaluated. The cut-off values of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio for predicting overall and progression-free survival were calculated using receiver operating characteristic curves.ResultsThe neutrophil-to-lymphocyte ratio, but not the platelet-to-lymphocyte ratio, was an independent prognostic factor. Patients with decreased neutrophil-to-lymphocyte ratio survived significantly longer than patients with increased neutrophil-to-lymphocyte ratio (median overall survival: 14.7 versus 10.4 months, P = 0.0110). Among patients with a low pre-treatment neutrophil-to-lymphocyte ratio, the overall survival did not differ significantly between those with decreased and those with increased neutrophil-to-lymphocyte ratio after 1 month (median: 19.0 versus 14.8 months, P = 0.1498). However, among patients with high pre-treatment neutrophil-to-lymphocyte ratio, those whose neutrophil-to-lymphocyte ratio decreased after 1 month showed significantly longer survival than those whose neutrophil-to-lymphocyte ratio increased (median: 12.7 versus 5.5 months, P < 0.0001). The therapeutic effect was not correlated with pre-treatment neutrophil-to-lymphocyte ratio or platelet-to-lymphocyte ratio.ConclusionsThe neutrophil-to-lymphocyte ratio is a prognostic factor, along with liver function and tumor markers, in patients with advanced hepatocellular carcinoma who received molecular-targeted agents as primary treatment. Thus, the neutrophil-to-lymphocyte ratio could be a prognostic biomarker for advanced hepatocellular carcinoma primarily treated with immunotherapy.
| S-EPMC7807940 | biostudies-literature