Identification and Validation of a Potential Stemness-Associated Biomarker in Hepatocellular Carcinoma.
Ontology highlight
ABSTRACT: Background
Cancer stem cells (CSCs) are typically related to metastasis, recurrence, and drug resistance in malignant tumors. However, the biomarker and mechanism of CSCs need further exploration. This study is aimed at comprehensively depicting the stemness characteristics and identify a potential stemness-associated biomarker in hepatocellular carcinoma (HCC).Methods
The data of HCC patients from The Cancer Genome Atlas (TCGA) were collected and divided based on the mRNA expression-based stemness index (mRNAsi) in this study. Weighted gene coexpression network analysis (WGCNA) and the protein-protein interaction (PPI) network were performed, and the genes were screened through the Cytoscape software. Then, we constructed a prognostic expression signature using the multivariable Cox analysis and verified using the GEO and ICGC databases. Even more importantly, we used the three-dimensional (3D) fibrin gel to enrich the tumor-repopulating cells (TRCs) to validate the expression of the signature in CSCs by quantitative RT-PCR.Results
mRNAsi was significantly elevated in tumor and high-mRNAsi score was associated with poor overall survival in HCC. The positive stemness-associated (blue) module with 737 genes were screened based on WGCNA, and Budding uninhibited by benzimidazoles 1 (BUB1) was identified as the hub gene highly related to stemness in HCC. Then, the prognostic value and stemness characteristics were well validated in the ICGC and GSE14520 cohorts. Further analysis showed the expression of BUB1 was elevated in TRCs.Conclusion
BUB1, as a potential stemness-associated biomarker, could serve as a therapeutic CSCs-target and predicted the clinical outcomes of patients with HCC.
SUBMITTER: Zhang Y
PROVIDER: S-EPMC9293570 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Metastasis is the major cause of hepatocellular carcinoma (HCC) mortality. Unfortunately, there are few reports on effective biomarkers for HCC metastasis. This study aimed to discover potential key genes of HCC, which could provide new insights for HCC metastasis. GEO (Gene Expression Omnibus) microarray and TCGA (The Cancer Genome Atlas) datasets were integrated to screen for candidate genes involved in HCC metastasis. Differentially expressed genes (DEGs) were screened, and then we performed enrichment analysis of Gene Ontology (GO), together with Kyoto Encyclopedia of Genes and Genomes (KEGG). A protein-protein interaction network was then built and analyzed utilizing STRING and Cytoscape, followed by the identification of 10 hub genes by cytoHubba. Four genes were associated with survival, their prognostic value was verified by prognostic signature analysis. Thymidylate synthase (TYMS) gene was identified as significant HCC metastasis-associated genes after mRNA expression validation and IHC analysis. TYMS silencing in HCC cells remarkedly inhibited growth and invasion. Finally, we found TYMS silencing dramatically decrease DNA synthesis and extracellular matrix (ECM) degradation, resulting in the inhibition of HCC metastasis, indicating TYMS had close associations with HCC development. These findings provided new insights into HCC metastasis and identified candidate gene prognosis signatures for HCC metastasis.
| S-EPMC8630669 | biostudies-literature
Project description:Hepatocellular Carcinoma (HCC) is one of the most common cancers in the world and it is often associated with poor prognosis. Liver transplantation and resection are two currently available curative therapies. However, most patients cannot be treated with such therapies due to late diagnosis. This underscores the urgent need to identify potential markers that ensure early diagnosis of HCC. As more evidences are suggesting that epigenetic changes contribute hepatocarcinogenesis, DNA methylation was poised as one promising biomarker. Indeed, genome wide profiling reveals that aberrant methylation is frequent event in HCC. Many studies showed that differentially methylated genes and CpG island methylator phenotype (CIMP) status in HCC were associated with clinicopathological data. Some commonly studied hypermethylated genes include p16, SOCS1, GSTP1 and CDH1. In addition, studies have also revealed that methylation markers could be detected in patient blood samples and associated with poor prognosis of the disease. Undeniably, increasing number of methylation markers are being discovered through high throughput genome wide data in recent years. Proper and systematic validation of these candidate markers in prospective cohort is required so that their actual prognostication and surveillance value could be accurately determined. It is hope that in near future, methylation marker could be translate into clinical use, where patients at risk could be diagnosed early and that the progression of disease could be more correctly assessed.
| S-EPMC4022334 | biostudies-other
Project description:BackgroundComplement factor H-related 4 (CFHR4) is a protein-coding gene that plays an essential role in multiple diseases. However, the prognostic value of CFHR4 in hepatocellular carcinoma (HCC) is unknown.MethodsUsing multiple databases, we investigated CFHR4 expression levels in HCC and multiple cancers. The relationship between CFHR4 expression levels and clinicopathological variables was further analyzed. Various potential biological functions and regulatory pathways of CFHR4 in HCC were identified by performing a Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and Gene Set Enrichment Analysis (GSEA). Single-sample gene set enrichment analysis (ssGSEA) was performed to confirm the correlation between CFHR4 expression and immune cell infiltration. The correlations between CFHR4 expression levels in HCC and N6-methyladenosine (m6A) modifications and the competing endogenous RNA (ceRNA) regulatory networks were confirmed in TCGA cohort.ResultsCFHR4 expression levels were significantly decreased in HCC tissues. Low CFHR4 expression in HCC tissues was significantly correlated with the patients' sex, race, age, TNM stage, pathological stage, tumor status, residual tumor, histologic grade and alpha fetal protein (AFP) level. GO and KEGG analyses revealed that differentially expressed genes related to CFHR4 may be involved in the synaptic membrane, transmembrane transporter complex, gated channel activity, chemical carcinogenesis, retinol metabolism, calcium signaling pathway, PPAR signaling pathway, insulin and gastric acid secretion. GSEA revealed that the FCGR-activated reaction, PLK1 pathway, ATR pathway, MCM pathway, cascade reactions of PI3K and FGFR1, reactant-mediated MAPK activation and FOXM1 pathway were significantly enriched in HCC with low CFHR4 expression. Moreover, CFHR4 expression was inversely correlated the levels of infiltrating Th2 cells, NK CD56bright cells and Tfh cells. In contrast, we observed positive correlations with the levels of infiltrating DCs, neutrophils, Th17 cells and mast cells. CFHR4 expression showed a strong correlation with various immunomarker groups in HCC. In addition, high CFHR4 expression significantly prolonged the overall survival (OS), disease-specific survival (DSS) and progression-free interval (PFI). We observed a substantial correlation between the expression of CFHR4 and multiple N6-methyladenosine genes in HCC and constructed potential CFHR4-related ceRNA regulatory networks.ConclusionsCFHR4 might be a potential therapeutic target for improving the HCC prognosis and is closely related to immune cell infiltration.
| S-EPMC9257081 | biostudies-literature
Project description:Methyltransferase-like 18 (METTL18), a METTL family member, is abundant in hepatocellular carcinoma (HCC). Studies have indicated the METTL family could regulate the progress of diverse malignancies while the role of METTL18 in HCC remains unclear. Data of HCC patients were acquired from the cancer genome atlas (TCGA) and gene expression omnibus (GEO). The expression level of METTL18 in HCC patients was compared with normal liver tissues by Wilcoxon test. Then, the logistic analysis was used to estimate the correlation between METTL18 and clinicopathological factors. Besides, Gene Ontology (GO), Gene Set Enrichment Analysis (GSEA), and single-sample Gene Set Enrichment Analysis (ssGSEA) were used to explore relevant functions and quantify the degree of immune infiltration for METTL18. Univariate and Multivariate Cox analyses and Kaplan-Meier analysis were used to estimate the association between METTL18 and prognosis. Besides, by cox multivariate analysis, a nomogram was conducted to forecast the influence of METTL18 on survival rates. METTL18-high was associated with Histologic grade, T stage, Pathologic stage, BMI, Adjacent hepatic tissue inflammation, AFP, Vascular invasion, and TP53 status (P < 0.05). HCC patients with METTL18-high had a poor Overall-Survival [OS; hazard ratio (HR): 1.87, P < 0.001), Disease-Specific Survival (DSS, HR: 1.76, P = 0.015), and Progression-Free Interval (PFI, HR: 1.51, P = 0.006). Multivariate analysis demonstrated that METTL18 was an independent factor for OS (HR: 2.093, P < 0.001), DSS (HR: 2.404, P = 0.015), and PFI (HR: 1.133, P = 0.006). Based on multivariate analysis, the calibration plots and C-indexes of nomograms showed an efficacious predictive effect for HCC patients. GSEA demonstrated that METTL18-high could activate G2M checkpoint, E2F targets, KRAS signaling pathway, and Mitotic Spindle. There was a positive association between the METTL18 and abundance of innate immunocytes (T helper 2 cells) and a negative relation to the abundance of adaptive immunocytes (Dendritic cells, Cytotoxic cells etc.). Finally, we uncovered knockdown of METTL18 significantly suppressed the proliferation, invasion, and migration of HCC cells in vitro. This research indicates that METTL18 could be a novel biomarker to evaluate HCC patients' prognosis and an important regulator of immune responses in HCC.
| S-EPMC8187872 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is one of the most common types of cancer, which is associated with a poor prognosis. It is necessary to identify novel prognostic biomarkers and therapeutic targets to improve the survival of patients with HCC. In the present study, a seven‑gene signature associated with HCC progression was identified using weighted gene co‑expression network analysis and least absolute shrinkage and selection operator, and its prognostic prediction value was confirmed in The Cancer Genome Atlas‑liver HCC and International Cancer Genome Consortium liver cancer‑RIKEN, Japan cohorts. Subsequently, a rarely reported gene, epoxide hydrolase 2 (EPHX2), was selected for further validation. Downregulation of EPHX2 in HCC was revealed using multiple expression datasets. Furthermore, reduced expression of EPHX2 was confirmed in HCC tissue samples and cell lines using reverse transcription‑quantitative polymerase chain reaction and western blotting. Additionally, Kaplan‑Meier survival curves indicated that patients with higher EPHX2 expression exhibited better prognosis, and clinicopathological analysis also revealed elevated EPHX2 levels in patients with early‑stage HCC. Notably, EPHX2 was identified as an independent prognostic biomarker for overall survival of patients with HCC. Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes analysis and gene set enrichment analysis were performed to elucidate the functions of EPHX2. The results suggested that EPHX2 expression was closely associated with metabolic reprogramming. Finally, the prognostic value of EPHX2 was evaluated using HCC tissue microarrays. In conclusion, downregulation of EPHX2 was significantly associated with the development of HCC; therefore, EPHX2 may be considered a putative therapeutic candidate for the targeted treatment of HCC.
| S-EPMC8299194 | biostudies-literature
Project description:Cancer stemness, referring to the stem-cell-like phenotype of cancer cells, has been recognised to play important roles in different aspects of hepatocarcinogenesis. A number of well-established cell-surface markers already exist for liver cancer stem cells, with potential new markers of liver cancer stem cells being identified. Both genetic and epigenetic factors that affect various signalling pathways are known to contribute to cancer stemness. In addition, the tumour microenvironment-both physical and cellular-is known to play an important role in regulating cancer stemness, and the potential interaction between cancer stem cells and their microenvironment has provided insight into the regulation of the tumour-initiating ability as well as the cellular plasticity of liver CSCs. Potential specific therapeutic targeting of liver cancer stemness is also discussed. With increased knowledge, effective druggable targets might be identified, with the aim of improving treatment outcome by reducing chemoresistance.
| S-EPMC7217836 | biostudies-literature
Project description:Purpose: Hepatocellular carcinoma (HCC) is a severe malignant tumor with high incidence and mortality. LncRNAs present broad clinical application prospects. Herein, we aim to identify a cancer stemness associated lncRNA and reveal its role in HCC diagnosis, prognosis evaluation, and progression. Methods: The cancer stemness-associated LINC02475 in HCC samples were identified using bioinformatics analysis. Cellular and molecular experiments were conducted to elucidate the role of LINC02475 in HCC. Results: The firm links between LINC02475 and HCC stemness and prognosis were demonstrated by bioinformatics analysis of public cancer datasets. LINC02475 expression was elevated in HCC, performed well in the diagnosis, and independently predicts poor overall survival (hazard ratio = 1.389, 95% confidence interval = 1.047-1.843, p = 0.023), as well as progression-free survival (hazard ratio = 1.396, 95% confidence interval = 1.016-1.917, p = 0.040) of HCC patients. Moreover, LINC02475 enhanced the tumorigenic pathways necessary for cell stemness, DNA replication required for cell proliferation, epithelial-mesenchymal transition involved in metastasis, and DNA damage repair pathways that drove cell radioresistance and cisplatin resistance, thus promoting HCC progression. Conclusion: Cancer stemness-associated LINC02475 independently predicted a poor prognosis and promoted HCC progression by enhancing stemness, proliferation, metastasis, radioresistance, and chemoresistance. Our study lays a foundation for the clinical application of LINC02475 as a novel biomarker and target for the diagnosis, prognosis evaluation, as well as treatment of HCC.
| S-EPMC9479154 | biostudies-literature
Project description:BackgroundHepatocellular carcinoma (HCC) is widely acknowledged as a malignant tumor with rapid progression, high recurrence rate, and poor prognosis. At present, there is a paucity of reliable biomarkers at the clinical level to guide the management of HCC and improve patient outcomes. Our research is aimed at assessing the prognostic value of MAD2L1 in HCC.MethodsFour datasets, GSE121248, GSE101685, GSE85598, and GSE62232, were selected from the GEO database to analyze differentially expressed genes (DEGs) between HCC and normal liver tissues. After functional analysis, we constructed a protein-protein interaction network (PPI) for DEGs and identified core genes in this network with high connectivity with other genes. We assessed the relationship between core genes and the pathogenesis and prognosis of HCC. Finally, we explored the gene regulatory signaling mechanisms involved in HCC pathogenesis.Results145 DEGs were screened from the intersection of the four GEO datasets. MAD2L1 was associated with most genes according to the PPI network and was selected as a candidate gene for further study. Survival analysis suggested that high MAD2L1 expression in HCC correlated with a worse prognosis. In addition, real-time quantitative PCR (RT-qPCR), western blot (WB), and immunohistochemistry (IHC) findings suggested that the expression of MAD2L1 was abnormally increased in HCC tissues and cells compared to paraneoplastic tissues and normal hepatocytes.ConclusionWe found that high MAD2L1 expression in HCC was significantly associated with overall patient survival and clinical features. We also explored the potential biological properties of this gene.
| S-EPMC8817109 | biostudies-literature
Project description:Increased glycolysis has been reported as a major metabolic hallmark in many cancers, and is closely related to malignant behavior of tumors. However, the potential mechanism of glycolysis in hepatocellular carcinoma (HCC) and its prognostic value are not well understood. To address this, we investigated glycolysis-related gene expression data of patients with HCC from TCGA and ICGC. Patients were categorized into three different glycolysis-associated subgroups: Glycolysis-M, Glycolysis-H, and Glycolysis-L. We found that Glycolysis-H combined with Glycolysis-M (Glycolysis-H+M) subgroup was associated with poor overall survival and distinct cancer stem cell characteristics and immune infiltrate patterns. Additionally, multiomics-based analyses were conducted to evaluate genomic patterns of glycolysis subgroups, including their gene mutations, copy number variations, and RNA-sequencing data. Finally, a glycolysis-associated multiomics prognostic model (GMPM) consisting of 19 glycolysis-associated genes was developed. The capability of GMPM in categorizing patients with HCC into high- and low-risk groups was validated with independent HCC datasets. Finally, GMPM was confirmed as an independent risk factor for the prognosis of patients with HCC. We believe that our findings provide new insights into the mechanism of glycolysis and highlight the potential clinical value of GMPM in predicting the prognosis of patients with HCC.
| S-EPMC7993684 | biostudies-literature
Project description:BackgroundThe aim of this study was to construct a model based on the prognostic features associated with epithelial-mesenchymal transition (EMT) to explore the various mechanisms and therapeutic strategies available for the treatment of metastasis and invasion by hepatocellular carcinoma (HCC) cells.MethodsEMT-associated genes were identified, and their molecular subtypes were determined by consistent clustering analysis. The differentially expressed genes (DEGs) among the molecular subtypes were ascertained using the limma package and they were subjected to functional enrichment analysis. The immune cell scores of the molecular subtypes were evaluated using ESTIMATE, MCPcounter, and GSCA packages of R. A multi-gene prognostic model was constructed using lasso regression, and the immunotherapeutic effects of the model were analyzed using the Imvigor210 cohort. In addition, immunohistochemical analysis was performed on a cohort of HCC tissue to validate gene expression.ResultsBased on the 59 EMT-associated genes identified, the 365-liver hepatocellular carcinoma (LIHC) samples were divided into two subtypes, C1 and C2. The C1 subtype mostly showed poor prognosis, had higher immune scores compared to the C2 subtype, and showed greater correlation with pathways of tumor progression. A four-gene signature construct was fabricated based on the 1130 DEGs among the subtypes. The construct was highly robust and showed stable predictive efficacy when validated using datasets from different platforms (HCCDB18 and GSE14520). Additionally, compared to currently existing models, our model demonstrated better performance. The results of the immunotherapy cohort showed that patients in the low-risk group have a better immune response, leading to a better patient's prognosis. Immunohistochemical analysis revealed that the expression levels of the FTCD, PON1, and TMEM45A were significantly over-expressed in 41 normal samples compared to HCC samples, while that of the G6PD was significantly over-expressed in cancerous tissues.ConclusionsThe four-gene signature construct fabricated based on the EMT-associated genes provides valuable information to further study the pathogenesis and clinical management of HCC.
| S-EPMC8613962 | biostudies-literature