Clinical Significance and Integrative Analysis of the SMC Family in Hepatocellular Carcinoma.
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ABSTRACT:
SUBMITTER: Nie H
PROVIDER: S-EPMC8437102 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex-derived reactive oxygen species (ROS) promote chronic liver inflammation and remodeling that can drive hepatocellular carcinoma development. The role of NOX expression in hepatocellular carcinoma (HCC) has been partially investigated; however, the clinical relevance of collective or individual NOX family member expression for HCC survival remains unclear. Here, we obtained NOX mRNA expression data for 377 HCC samples and 21 normal liver controls from the TCGA data portal and performed Kaplan-Meier survival, gene ontology functional enrichment, and gene set enrichment analyses. Although most NOX genes exhibited little change, some were significantly induced in HCC compared to that in normal controls. In addition, HCC survival analyses indicated better overall survival in patients with high NOX4 and DUOX1 expression, whereas patients with high NOX1/2/5 expression showed poor prognoses. Gene-neighbour and gene set enrichment analyses revealed that NOX1/2/5 were strongly correlated with genes associated with cancer cell survival and metastasis, whereas increased NOX4 and DUOX1 expression was associated with genes that inhibit tumour progression. On the basis of these data, NOX family gene expression analysis could be a predictor of survival and identify putative therapeutic targets in HCC.
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Project description:BackgroundKinesin family member 18B (KIF18B) is a member of the kinesin-8 superfamily, and functions as an oncogene in human cancers. However, its expression profile and role in lung adenocarcinoma (LUAD) remain unclear.Materials and methodsWe examined the expression profile of KIF18B using quantitative real-time reverse transcription polymerase chain reaction and immunohistochemistry in fresh clinical samples. Using data downloaded from the Cancer Genome Atlas database and Gene Expression Omnibus, we explored the clinical significance of KIF18B, potential mechanisms of its dysregulation and its underlying biological function in LUAD.ResultsKIF18B was significantly over-expressed in LUAD tissues relative to normal tissues. High KIF18B expression was associated with smoking history, positive nodal invasion, advanced clinical stage, death status and poorer prognosis. Cox regression analyses revealed that KIF18B overexpression was an independent prognostic biomarker for poor overall survival (OS) and recurrence-free survival in LUAD. In addition, KIF18B mutation was observed in 2.2% of LUAD cases. DNA copy number variation was correlated with upregulated expression of KIF18B in LUAD tissues and cell lines. The methylation level of some KIF18B DNA CpG sites was negatively associated with its mRNA expression. KIF18B was predictively targeted by miR-125a-5p, which was downregulated in LUAD tissues, inversely correlated with KIF18B mRNA expression and significantly associated with poor OS. Furthermore, gene set enrichment analysis revealed that genes positively co-expressed with KIF18B were mainly enriched in cell cycle signaling pathways.ConclusionOur results indicate that KIF18B is a promising prognostic biomarker for LUAD. DNA amplification, hypomethylation as well as miR-125a-5p downregulation may be involved in the mechanism of KIF18B dysregulation in LUAD. KIF18B might function as a novel oncogene through cell cycle regulation pathways in LUAD.
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Project description:Background: Hepatocellular carcinoma (HCC), which is the most common type of primary liver cancer, often presents at advanced stage with a dismal prognosis. Novel tumor biomarkers are needed to aid in HCC early detection and prognostication. Methods: Immunohistochemical staining for RecQ-mediated genome instability protein 2 (RMI2) was performed in 330 surgically resected HCC specimens and 190 adjacent normal tissues. Univariate and multivariate regression analysis were applied to identify prognostic indicators of HCC outcomes. Patient's survival was assessed with the Kaplan-Meier method. Results: RMI2 in HCC tissue was significantly higher than that in adjacent normal tissues, and was positively correlated with HCC histological grade and stage (P < .05) but negatively correlated with the survival period. RIM2 was identified to be an independent prognostic indicator for HCC. Conclusion: The abnormal expression of RMI2 may be related to the occurrence and development of HCC. RIM2 could potentially serve as a novel tumor-specific biomarker for HCC diagnosis and prognosis prediction.
| S-EPMC8516379 | biostudies-literature
Project description:Recent findings from The Cancer Genome Atlas project have provided a comprehensive map of genomic alterations that occur in hepatocellular carcinoma (HCC), including unexpected mutations in apolipoprotein B (APOB). We aimed to determine the clinical significance of this non-oncogenetic mutation in HCC. An Apob gene signature was derived from genes that differed between control mice and mice treated with siRNA specific for Apob (1.5-fold difference; P < 0.005). Human gene expression data were collected from four independent HCC cohorts (n = 941). A prediction model was constructed using Bayesian compound covariate prediction, and the robustness of the APOB gene signature was validated in HCC cohorts. The correlation of the APOB signature with previously validated gene signatures was performed, and network analysis was conducted using ingenuity pathway analysis. APOB inactivation was associated with poor prognosis when the APOB gene signature was applied in all human HCC cohorts. Poor prognosis with APOB inactivation was consistently observed through cross-validation with previously reported gene signatures (NCIP A, HS, high-recurrence SNUR, and high RS subtypes). Knowledge-based gene network analysis using genes that differed between low-APOB and high-APOB groups in all four cohorts revealed that low-APOB activity was associated with upregulation of oncogenic and metastatic regulators, such as HGF, MTIF, ERBB2, FOXM1, and CD44, and inhibition of tumor suppressors, such as TP53 and PTEN. In conclusion, APOB inactivation is associated with poor outcome in patients with HCC, and APOB may play a role in regulating multiple genes involved in HCC development.
| S-EPMC6235894 | biostudies-literature
Project description:BACKGROUND:Hepatocellular carcinoma (HCC) is the major type of primary liver cancer. Intrahepatic metastasis, such as portal vein tumor thrombosis (PVTT), strongly indicates poor prognosis of HCC. But now, there are limited understandings of the molecular features and mechanisms of those metastatic HCCs. METHODS:To characterize the molecular alterations of the metastatic HCCs, we implemented an integrative analysis of the copy number variations (CNVs), DNA methylations and transcriptomes of matched adjacent normal, primary tumor and PVTT samples from 19 HCC patients. RESULTS:CNV analysis identified a frequently amplified focal region chr11q13.3 and a novel deletion peak chr19q13.41 containing three miRNAs. The integrative analysis with RNA-seq data suggests that CNVs and differential promoter methylations regulate distinct oncogenic processes. Then, we used individualized differential analysis to identify the differentially expressed genes between matched primary tumor and PVTT of each patient. Results show that 5 out of 19 studied patients acquire evidential progressive alterations of gene expressions (more than 1000 differentially expressed genes were identified in each patient). While, another subset of eight patients have nearly identical gene expressions between the corresponding matched primary tumor and PVTT. Twenty genes were found to be recurrently and progressively differentially expressed in multiple patients. These genes are mainly associated with focal adhesion, xenobiotics metabolism by cytochrome P450 and amino acid metabolism. For several differentially expressed genes in metabolic pathways, their expressions are significantly associated with overall survivals and vascular invasions of HCC patients. The following transwell assay experiments validate that they can regulate invasive phenotypes of HCC cells. CONCLUSIONS:The metastatic HCCs with PVTTs have significant molecular alterations comparing with adjacent normal tissues. The recurrent alteration patterns are similar to several previously published general HCC cohorts, but usually with higher severity. By an individualized differential analysis strategy, the progressively differentially expressed genes between the primary tumor and PVTT were identified for each patient. A few patients aquire evidential progressive alterations of gene expressions. And, experiments show that several recurrently differentially expressed genes can strongly regulate HCC cell invasions.
| S-EPMC6854708 | biostudies-literature
Project description:NLRC5, the largest member of the nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family, has been reported to participate in the regulation of immune function and is associated with chronic inflammatory diseases. However, the biological function of NLRC5 in hepatocellular carcinoma (HCC) has not been fully demonstrated. The aim of this study is to evaluate NLRC5 expression in the tumor tissues of HCC patients undergoing surgical treatment, assess its prognostic value, and explore its relationship with critical immune-related molecules within the tumor microenvironment. A total of 100 patients with hepatitis B virus-associated HCC receiving surgical treatment were enrolled in the study. Immunohistochemical results were obtained by scoring the intensity of cellular staining and the percentage of positive cells in the tissue sections. The association between NLRC5 expression levels and the main clinicopathological factors was analyzed by Chi-square test method. The prognostic values were analyzed by COX regression model and the Kaplan-Meier survival curve. Receiver operating characteristic (ROC) curve analysis was performed to assess the predictive performance of NLRC5 in postoperative patients with HCC. IHC showed that high expression of NLRC5 was observed in 67% of HCC tissue samples. Chi-square test showed that NLRC5 was a risk factor associated with tumor number, satellite nodule, and envelope invasion. Kaplan-Meier survival curves and COX survival analysis showed that high expression of NLRC5 was significantly associated with decreased overall survival (OS) in HCC patients (HR = 1.79, 95% CI 1.03-3.12, p = .041). However, univariate logistic regression analysis revealed that NLRC5 showed positive relationship with GZMB and CD8α suggesting its role in immune escape of HCC. ROC curve analysis showed that the combination of tumor number, envelope invasion, and NLRC5 expression (area under the curve = 0.824, sensitivity = 77.30%, specificity = 82.4%) can more accurately evaluate the prognosis of HCC patients compared to the combination of only tumor number and envelope invasion (area under the curve = 0.690, sensitivity = 43.9%, specificity = 94.1%).NLRC5 plays a crucial role in progression of HCC and can be considered as a potential prognostic and predictive biomarker. Targeting NLRC5 may provide an attractive therapeutic approach for HCC.
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Project description:To study the clinical significance of HINT2 expression in patients with HCC.We investigated HINT2 mRNA expression in tumors and adjacent non-tumor hepatic tissues from 106 HCC patients using quantitative real-time PCR. Appropriate statistical methods were then applied to assess the relationships between the HINT2 mRNA level and clinical parameters.HINT2 was significantly down-regulated in HCC (P < .0001). No significant correlation was found between HINT2 expression and clinicopathological factors in HCC patients. A Kaplan-Meier survival curve showed that HINT2 expression is related to recurrence-free survival (P < .05). Multivariate analyses revealed that tumor size and HINT2 expression are risk factors for HCC recurrence.HINT2 is down-regulated in HCC, and low HINT2 expression predicts earlier tumor recurrence. HINT2 expression may serve as a prognostic indicator of recurrence in HCC.
| S-EPMC6890357 | biostudies-literature
Project description:microRNA (miRNA) expression profiles varied greatly among current studies due to different technological platforms and small sample size. Systematic and integrative analysis of published datesets that compared the miRNA expression profiles between hepatocellular carcinoma (HCC) tissue and paired adjacent noncancerous liver tissue was performed to determine candidate HCC associated miRNAs. Moreover, we further validated the confirmed miRNAs in a clinical setting using qRT-PCR and Tumor Cancer Genome Atlas (TCGA) dataset. A miRNA integrated-signature of 5 upregulated and 8 downregulated miRNAs was identified from 26 published datesets in HCC using robust rank aggregation method. qRT-PCR demonstrated that miR-93-5p, miR-224-5p, miR-221-3p and miR-21-5p was increased, whereas the expression of miR-214-3p, miR-199a-3p, miR-195-5p, miR-150-5p and miR-145-5p was decreased in the HCC tissues, which was also validated on TCGA dataset. A miRNA based score using LASSO regression model provided a high accuracy for identifying HCC tissue (AUC = 0.982): HCC risk score = 0.180E_miR-221 + 0.0262E_miR-21 - 0.007E_miR-223 - 0.185E_miR-130a. E_miR-n = Log 2 (expression of microRNA n). Furthermore, expression of 5 miRNAs (miR-222, miR-221, miR-21 miR-214 and miR-130a) correlated with pathological tumor grade. Cox regression analysis showed that miR-21 was related with 3-year survival (hazard ratio [HR]: 1.509, 95%CI: 1.079-2.112, P = 0.016) and 5-year survival (HR: 1.416, 95%CI: 1.057-1.897, P = 0.020). However, none of the deregulated miRNAs was related with microscopic vascular invasion. This study provides a basis for further clinical application of miRNAs in HCC.
| S-EPMC4694817 | biostudies-literature
Project description:ObjectiveThis study aims to build a prognostic model of hepatocellular carcinoma (HCC) with ferroptosis-associated genes and explore their molecular function.MethodsGene expression data and clinical information were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases and the International Cancer Genome Consortium (ICGC). A ferroptosis-associated gene set was obtained from the FerrDb database to identify differentially expressed genes. Then, we performed pathway enrichment analysis and immune infiltration analysis. A combined model based on ferroptosis-associated genes for predicting the overall survival of HCC was built by univariate and multivariate Cox regression analyses. Quantitative real-time polymerase chain reaction, Western blotting, colony formation, CCK-8, and EdU incorporation assays were performed to clarify the function of CAPG in the regulation of cell proliferation in human HCC. Ferroptosis was evaluated by glutathione (GSH), malondialdehyde (MDA), and total iron detection.ResultsForty-nine ferroptosis-related genes were significantly correlated with HCC, 19 of which had prognostic significance. CAPG, SLC7A11 and SQSTM1 were used to construct a novel risk model. The areas under the curves (AUCs) were 0.746 and 0.720 (1 year) in the training and validation groups, respectively. The survival analysis indicated that patients with high risk scores exhibited worse survival in the training and validation groups. The risk score was also identified as an independent prognostic factor of overall survival (OS), which established and validated the predictive abilities of the nomogram. The risk score was also significantly correlated with the expression of immune checkpoint genes. In vitro data showed that CAPG knockdown dramatically suppressed HCC cell proliferation, and the underlying molecular mechanisms might be that the silencing of CAPG reduced the expression of SLC7A11 and promoted ferroptosis.ConclusionThe established risk model can be used to predict the prognosis of HCC. At the mechanistic level, CAPG may drive HCC progression by regulating SLC7A11, and ferroptosis activation in HCC patients with high CAPG expression may serve as a potential therapeutic strategy.
| S-EPMC10192498 | biostudies-literature
Project description: Not available
| S-DIXA-D-1002 | biostudies-other