Integrative analysis reveals the prognostic value and functions of splicing factors implicated in hepatocellular carcinoma.
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ABSTRACT:
SUBMITTER: Wang Y
PROVIDER: S-EPMC8313569 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Overexpression of Golgi membrane protein 1 (GOLM1) is closely associated with hepatocellular carcinoma (HCC) vascular invasion. How GOLM1 may be involved in angiogenesis in HCC remains unclear. We explored how GOLM1 promotes angiogenesis in HCC and potential prognostic value. Expression levels of GOLM1 in HCC patients and healthy controls were obtained from The Cancer Genome Atlas (TCGA). Differentially expressed genes (DEGs) between HCC patients and controls were compared. GOLM1 was knocked out in the HCC cell line, and RNA sequencing and DEG expression analysis were performed compared with control cells. Based on TCGA data and cell line RNA sequencing data, DEGs affected by a high expression of GOLM1 were identified. Subsequently, enrichment analysis was performed to explore the functions and pathways of the DEGs affected by a high expression of GOLM1. A relevant network analysis was built. Cox regression, genomic variance analysis scores, minimum absolute shrinkage and selection operator regression, and random forest regression models were applied to determine the best prognostic model and validated using the GSE54236 dataset from the Gene Expression Omnibus (GEO). We determined the effect of GOLM1 expression on immune cell infiltration in liver cancer. GOLM1 was overexpressed in HCC tissues compared with controls, and its level correlated with tumor purity and prognosis. 400 DEGs affected by highly expressed GOLM1 were identified in TCGA and cell line RNA sequencing data. Enrichment analysis revealed that these DEGs may be related to biological processes of oxidative stress and angiogenesis and involved in the VEGF signaling pathway and protein processing in endoplasmic reticulum. We predicted a comprehensive regulatory network in which GOLM1 activated VEGF signaling to promote HCC angiogenesis. GOLM1 may interact with E2F1 and IGF2BP3 to promote angiogenesis. GOLM1 overexpression was associated with greater immune cell infiltration. A random forest regression model was the best prognostic model. Our study reveals a potential molecular mechanism of GOLM1 in promoting HCC. We developed two prognostic models based on DEG associated with GOLM1 overexpression to help stratify HCC prognosis and improve individualized treatment.
| S-EPMC9535134 | biostudies-literature
Project description:Prefoldins (PFDNs), a group of proteins known to be associated with cytoskeletal rearrangement, are involved in tumor progression in various cancer types. However, little is known about the roles of PFDNs in hepatocellular carcinoma (HCC). Herein, we investigated the transcriptional and survival data of PFDNs from The Cancer Genome Atlas (TCGA) database. Gene Ontology (GO), Gene Set Enrichment Analysis (GSEA), and single-sample gene set enrichment analysis (ssGSEA) were used to evaluate the potential functions of PFDN1/2/3/4. We also detected the expression of PFDN1/2/3/4 via immunohistochemistry (IHC), Western blotting, and real-time PCR in our clinical samples. We found that the PFDN family showed elevated expression in HCC tissues, while only PFDN1/2/3/4 were found to be significantly correlated with poor prognosis of patients with HCC in the TCGA database. Further investigation was associated with PFDN1-4. We found that the expression of PFDN1/2/3/4 was significantly associated with advanced clinicopathologic features. Apart from the TCGA database, IHC, real-time PCR, and immunoblotting identified the overexpression of PFDN1/2/3/4 in HCC tissues and HCC cell lines. Taken together, these results indicated that PFDN1/2/3/4 might be novel prognostic biomarkers and treatment targets for patients with HCC.
| S-EPMC9691963 | biostudies-literature
Project description:The recurrence of hepatocellular carcinoma, the sixth most common neoplasm and the third leading cause of cancer-related mortality worldwide, represents an important clinical problem, since it may occur after both surgical and medical treatment. The recurrence rate involves 2 phases: an early phase and a late phase. The early phase usually occurs within 2 years after resection; it is mainly related to local invasion and intrahepatic metastases and, therefore, to the intrinsic biology of the tumor. On the other hand, the late phase occurs more than 2 years after surgery and is mainly related to de novo tumor formation as a consequence of the carcinogenic cirrhotic environment. Since recent studies have reported that early and late recurrences may have different risk factors, it is clinically important to recognize these factors in the individual patient as soon as possible. The aim of this review was, therefore, to identify predicting factors for the recurrence of hepatocellular carcinoma, by means of invasive and non-invasive methods, according to the different therapeutic strategies available. In particular the role of emerging techniques (e.g., transient elastography) and biological features of hepatocellular carcinoma in predicting recurrence have been discussed. In particular, invasive methods were differentiated from non-invasive ones for research purposes, taking into consideration the emerging role of the genetic signature of hepatocellular carcinoma in order to better allocate treatment strategies and surveillance follow-up in patients with this type of tumor.
| S-EPMC4033434 | biostudies-other
Project description:BackgroundHepatocellular carcinoma (HCC) was the sixth common malignancies characteristic with highly aggressive in the world. It was well established that tumor mutation burden (TMB) act as indicator of immunotherapeutic responsiveness in various tumors. However, the role of TMB in tumor immune microenvironment (TIME) is still obscure.MethodThe mutation data was analyzed by employing "maftools" package. Weighted gene co-expression network analysis (WGCNA) was implemented to determine candidate module and significant genes correlated with TMB value. Differential analysis was performed between different level of TMB subgroups employing R package "limma". Gene ontology (GO) enrichment analysis was implemented with "clusterProfiler", "enrichplot" and "ggplot2" packages. Then risk score signature was developed by systematical bioinformatics analyses. K-M survival curves and receiver operating characteristic (ROC) plot were further analyzed for prognostic validity. To depict comprehensive context of TIME, XCELL, TIMER, QUANTISEQ, MCPcounter, EPIC, CIBERSORT, and CIBERSORT-ABS algorithm were employed. Additionally, the potential role of risk score on immune checkpoint blockade (ICB) immunotherapy was further explored. The quantitative real-time polymerase chain reaction was performed to detect expression of HTRA3.ResultsTMB value was positively correlated with older age, male gender and early T status. A total of 75 intersection genes between TMB-related genes and differentially expressed genes (DEGs) were screened and enriched in extracellular matrix-relevant pathways. Risk score based on three hub genes significantly affected overall survival (OS) time, infiltration of immune cells, and ICB-related hub targets. The prognostic performance of risks score was validated in the external testing group. Risk-clinical nomogram was constructed for clinical application. HTRA3 was demonstrated to be a prognostic factor in HCC in further exploration. Finally, mutation of TP53 was correlated with risk score and do not interfere with risk score-based prognostic prediction.ConclusionCollectively, a comprehensive analysis of TMB might provide novel insights into mutation-driven mechanism of tumorigenesis further contribute to tailored immunotherapy and prognosis prediction of HCC.
| S-EPMC8254981 | biostudies-literature
Project description:Alternative splicing events (ASEs) play a role in cancer development and progression. We investigated whether ASEs are prognostic for overall survival (OS) in hepatocellular carcinoma (HCC). RNA sequencing data was obtained for 343 patients included in The Cancer Genome Atlas. Matched splicing event data for these patients was then obtained from the TCGASpliceSeq database, which includes data for seven types of ASEs. Univariate and multivariate Cox regression analysis demonstrated that 3,814 OS-associated splicing events (OS-SEs) were correlated with OS. Prognostic indices were developed based on the most significant OS-SEs. The prognostic index based on all seven types of ASEs (PI-ALL) demonstrated superior efficacy in predicting OS of HCC patients at 2,000 days compared to those based on single ASE types. Patients were stratified into two risk groups (high and low) based on the median prognostic index. Kaplan-Meier survival analysis demonstrated that PI-ALL had the greatest capacity to distinguish between patients with favorable vs. poor outcomes. Finally, univariate Cox regression analysis demonstrated that the expression of 23 splicing factors was correlated with OS-SEs in the HCC cohort. Our data indicate that a prognostic index based on ASEs is prognostic for OS in HCC.
| S-EPMC6660027 | biostudies-literature
Project description: Not available
| S-DIXA-D-1002 | biostudies-other
Project description:Numerous articles reported that dysregulated expression levels of miRNAs correlated with survival time of HCC patients. However, there has not been a comprehensive meta-analysis to evaluate the accurate prognostic value of miRNAs in HCC.Meta-analysis.Studies, published in English, estimating expression levels of miRNAs with any survival curves in HCC were identified up until 15 April, 2017 by performing online searches in PubMed, EMBASE, Web of Science and Cochrane Database of Systematic Reviews by two independent authors. The pooled hazard ratios (HR) with 95% confidence intervals (CI) were used to estimate the correlation between miRNA expression and overall survival (OS).54 relevant articles about 16 miRNAs, with 6464 patients, were ultimately included. HCC patients with high expression of tissue miR-9 (HR = 2.35, 95% CI = 1.46-3.76), miR-21 (HR = 1.76, 95% CI = 1.29-2.41), miR-34c (HR = 1.64, 95% CI = 1.05-2.57), miR-155 (HR = 2.84, 95% CI = 1.46-5.51), miR-221 (HR = 1.76, 95% CI = 1.02-3.04) or low expression of tissue miR-22 (HR = 2.29, 95% CI = 1.63-3.21), miR-29c (HR = 1.35, 95% CI = 1.10-1.65), miR-34a (HR = 1.84, 95% CI = 1.30-2.59), miR-199a (HR = 2.78, 95% CI = 1.89-4.08), miR-200a (HR = 2.64, 95% CI = 1.86-3.77), miR-203 (HR = 2.20, 95% CI = 1.61-3.00) have significantly poor OS (P < 0.05). Likewise, HCC patients with high expression of blood miR-21 (HR = 1.73, 95% CI = 1.07-2.80), miR-192 (HR = 2.42, 95% CI = 1.15-5.10), miR-224 (HR = 1.56, 95% CI = 1.14-2.12) or low expression of blood miR-148a (HR = 2.26, 95% CI = 1.11-4.59) have significantly short OS (P < 0.05).In conclusion, tissue miR-9, miR-21, miR-22, miR-29c, miR-34a, miR-34c, miR-155, miR-199a, miR-200a, miR-203, miR-221 and blood miR-21, miR-148a, miR-192, miR-224 demonstrate significantly prognostic value. Among them, tissue miR-9, miR-22, miR-155, miR-199a, miR-200a, miR-203 and blood miR-148a, miR-192 are potential prognostic candidates for predicting OS in HCC.
| S-EPMC5739810 | biostudies-other
Project description:Previous studies have demonstrated the role of abnormal alternative splicing (AS) in tumor progression. This study examines the prognostic index (PI) of alternative splices (ASs) in patients with hepatocellular carcinoma (HCC). The clinical features and splicing events of patients with HCC were downloaded from The Cancer Genome Atlas (TCGA). Differentially expressed AS (DEAS) were compared between HCC and adjacent normal samples. Univariate Cox regression analysis was used to determine changes in DEAS associated with overall survival (OS). A PI was generated from OS-associated DEASs using Kaplan-Meier curves, receiver operating characteristic (ROC) curves, multivariate Cox regression, and cluster analysis. Then, the correlation between DEASs and splicing factors was assessed, followed by functional and pathway enrichment analysis. We identified 34 163 ASs of 8985 genes in HCC, and 153 OS-ASs were identified using univariate Cox regression analysis. Low- and high-PI groups were determined based on the median "PI-ALL" value according to significantly different survival (P = 2.2e - 16). The ROC curve of all PI (PI-ALL) had an area under the curve (AUC) of 0.993 for survival status in patients with HCC. A potential regulatory network associated with prognosis of patients with HCC was established. Enrichment analysis also resulted in the identification of several pathways potentially associated with carcinogenesis and progression of HCC. Four clusters were identified that were associated with clinical features and prognosis. Our study generated comprehensive profiles of ASs in HCC. The interaction network and functional connections were used to elucidate the underlying mechanisms of AS in HCC.
| S-EPMC7064038 | biostudies-literature
Project description:Accumulating evidence indicates an unexpected role of aberrant splicing in hepatocellular carcinoma (HCC) that has been seriously neglected in previous studies. There is a need for a detailed analysis of alternative splicing (AS) and its underlying biological and clinical relevance in HCC. In this study, clinical information and corresponding RNA sequencing data of HCC patients were obtained from The Cancer Genome Atlas. Percent spliced in (PSI) values and transcriptional splicing patterns of genes were determined from the original RNA sequencing data using SpliceSeq. Then, based on the PSI values of AS events in different patients, a series of bioinformatics methods was used to identify differentially expressed AS events (DEAS), determine potential regulatory relationships, and investigate the correlation between DEAS and the patients' clinicopathological features. Finally, 25,934 AS events originating from 8,795 genes were screened with high reliability; 263 of these AS events were identified as DEAS. The parent genes of these DEAS formed an intricate network with roles in the regulation of cancer-related pathway and liver metabolism. In HCC, 36 splicing factors were involved in the dysregulation of part DEAS, 100 DEAS events were correlated with overall survival, and 71 DEAS events were correlated with disease-free survival. Stratifying HCC patients according to DEAS resulted in four clusters with different survival patterns. Significant variations in AS occurred during HCC initiation and maintenance; these are likely to be vital both for biological processes and in prognosis. The HCC-related AS events identified here and the splicing networks constructed will be valuable in deciphering the underlying role of AS in HCC.
| S-EPMC7432180 | biostudies-literature
Project description:BackgroundDespite advances in multiple disciplinary diagnoses and treatments, the prognosis of hepatocellular carcinoma (HCC) remains poor. Some evidence has identified that the aberrant expression of tropomyosins (TPMs) is involved with some cancers development. However, prognostic values of TPMs in HCC have not been thoroughly investigated.MethodsOriginal TPM1-4 mRNA expression of TCGA HCC data and GTEx was downloaded from UCSC XENA. Oncomine database and GSE46408 were used for verification. Clinical stages and survival analysis of TPM1-4 in HCC were performed by GEPIA2. cBioPortal was utilized to assess TPM1-4 gene alteration in HCC. TIMER2.0 was used for investigating the relevance of TPM1-4 to tumor-infiltrating immune cells in HCC. Additionally, we constructed a TPM1-4 prognostic model to explore the value of TPM1-4 for prognostic evaluation in HCC. LinkedOmics was applied to elucidate TPM3 co-expression networks in HCC.ResultsThis present study showed that TPM1-4 was upregulated in all HCC tissues, and TPM3 overexpression was correlated with poor survival outcomes in patients with HCC. Besides, TPM3 amplification was the main altered type in TPM1-4 genetic alteration, which affected the prognosis of HCC patients. The risk model revealed that TPM1, TPM2, and TPM3 were applied to risk assessment of HCC prognosis, among which TPM3 expression was significantly higher in the high-risk group than that in the low-risk group. Univariate and multivariate cox regression analyses indicated that TPM3 may be an independent prognostic factor of HCC prognosis. In addition, TPM3 co-expression genes mainly participated in the cell cycle by maintaining microtubule cytoskeleton in HCC progression. TPM1-4 was associated with some tumor-infiltrating immune cells in HCC.ConclusionOur study detected that the expression level of TPM1-4 was all remarkably elevated in HCC, suggesting that TPM1-4 may serve an important role in HCC development. High TPM3 expression was found to be correlated with poor overall survival, and TPM3 may be an independent prognostic factor for HCC.
| S-EPMC8729055 | biostudies-literature