Overall Survival Of Hepatocellular Carcinoma Patients Research Articles

SSR2 overexpression associates with tumorigenesis and metastasis of Hepatocellular Carcinoma through modulating EMT.

Background: Hepatocellular carcinoma (HCC) is a common malignancy around the world. The molecular mechanisms underlying HCC tumorigenesis and metastasis are far from clear. Numerous studies have pointed out that signal sequence receptor (SSR) is an endoplasmic reticulum-related protein involved in protein folding and processing of eukaryotic cells. SSR2 is a subunit of SSR protein, but the role of SSR2 in hepatocellular carcinoma is largely unknown and warrants further study.Materials and Methods: Several public databases were data mined to analyze the expression of four subunits of SSR between tumor and its peritumor counterparts. Also, the expression of SSR2 in our own collected tissues from HCC patients were analyzed by IHC and quantitative PCR. Survival analyses were conducted to delineate the prognostic value of SSR2. Clinical data were obtained followed by analysis based on SSR2 expression. Afterwards, cell proliferation, migration and invasion were detected by IncuCyte and trans-well assays, respectively. RNA interference was carried out by transfecting specific siRNA targeting SSR2 into cells using lipo2000. Western blot was applied to validate the knockdown effect and regulation on EMT-related proteins.Results: We examined the expression of SSR and its correlation with recurrence and survival of patients. We discovered that SSR2 overexpression was negatively associated with survival of HCC patients from TCGA databases and the mutation of SSR2 was most among the four subunits of SSR protein. Additionally, in this study, we collected tumor and adjacent tissues from 125 cases of HCC patients. Through constructing tissue microarray, we have identified that SSR2 was highly expressed in HCC tumor tissues compared with adjacent normal tissues of hepatocellular carcinoma patients by immunohistochemistry assays. Furthermore, Kaplan-Meier survival analysis from our collected tissues revealed that the overexpression of SSR2 was inversely correlated with disease free survival and overall survival of HCC patients. We elucidated that SSR2 promotes proliferation, migration and invasion of HCC cells. SSR2 knockdown suppressed epithelial mesenchymal transition (EMT) of HCC cells.Conclusions: These results collectively show that SSR2 is overexpressed in HCC tumor tissues, and it is an important factor in predicting survival of HCC patients. Additionally, it is involved in metastasis of HCC. These findings may help to exploit SSR2 as a novel factor in predicting prognosis and metastasis of HCC.

GTSE1, CDC20, PCNA, and MCM6 Synergistically Affect Regulations in Cell Cycle and Indicate Poor Prognosis in Liver Cancer

GTSE1 is well correlated with tumor progression; however, little is known regarding its role in liver cancer prognosis. By analyzing the hepatocellular carcinoma (HCC) datasets in GEO and TCGA databases, we showed that high expression of GTSE1 was correlated with advanced pathologic stage and poor prognosis of HCC patients. To investigate underlying molecular mechanism, we generated GTSE1 knockdown HCC cell line and explored the effects of GTSE1 deficiency in cell growth. Between GTSE1 knockdown and wild-type HCC cells, we identified 979 differentially expressed genes (520 downregulated and 459 upregulated genes) in the analysis of microarray-based gene expression profiling. Functional enrichment analysis of DEGs suggested that S phase was dysregulated without GTSE1 expression, which was further verified from flow cytometry analysis. Moreover, three other DEGs: CDC20, PCNA, and MCM6, were also found contributing to GTSE1-related cell cycle arrest and to be associated with poor overall survival of HCC patients. In conclusion, GTSE1, together with CDC20, PCNA, and MCM6, may synergistically promote adverse prognosis in HCC by activating cell cycle. Genes like GTSE1, CDC20, PCNA, and MCM6 may be promising prognostic molecular biomarkers in liver cancer.

Systematic analysis and prediction model construction of alternative splicing events in hepatocellular carcinoma: a study on the basis of large-scale spliceseq data from The Cancer Genome Atlas.

Growing evidence showed that alternative splicing (AS) event is significantly related to tumor occurrence and progress. This study was performed to make a systematic analysis of AS events and constructed a robust prediction model of hepatocellular carcinoma (HCC). The clinical information and the genes expression profile data of 335 HCC patients were collected from The Cancer Genome Atlas (TCGA). Information of seven types AS events were collected from the TCGA SpliceSeq database. Overall survival (OS) related AS events and splicing factors (SFs) were identified using univariate Cox regression analysis. The corresponding genes of OS-related AS events were sent for gene network analysis and functional enrichment analysis. Optimal OS-related AS events were selected by LASSO regression to construct prediction model using multivariate Cox regression analysis. Prognostic value of the prediction models were assessed by receiver operating characteristic (ROC) curve and KaplanMeir survival analysis. The relationship between the Percent Spliced In (PSI) value of OS-related AS events and SFs expression were analyzed using Spearman correlation analysis. And the regulation network was generated by Cytoscape. A total of 34,163 AS events were identified, which consist of 3,482 OS-related AS events. UBB, UBE2D3, SF3A1 were the hub genes in the gene network of the top 800 OS-related AS events. The area under the curve (AUC) of the final prediction model based on seven types OS-related AS events was 0.878, 0.843, 0.821 in 1, 3, 5 years, respectively. Upon multivariate analysis, risk score (All) served as the risk factor to independently predict OS for HCC patients. SFs HNRNPH3 and HNRNPL were overexpressed in tumor samples and were signifcantly associated with the OS of HCC patients. The regulation network showed prominent correlation between the expression of SFs and OS-related AS events in HCC patients. The final prediction model performs well in predicting the prognosis of HCC patients. And the findings in this study improve our understanding of the association between AS events and HCC.

Clinical significance and function of RDH16 as a tumor-suppressing gene in hepatocellular carcinoma.

Our previous transcriptome sequencing analysis detected that retinol dehydrogenase16 (RDH16) was dramatically downregulated in hepatocellular carcinoma (HCC). RDH16 belongs to the short-chain dehydrogenases/reductases super family, and its role in HCC remains unknown. This study aimed to investigate the expression and function of RDH16 in HCC. The mRNA and protein level of RDH16 in HCC samples were detected by quantitative real-time polymerase chain reaction and immunohistochemistry analyses, respectively. The role of RDH16 in HCC was determined by invitro and invivo functional studies. Downregulation of RDH16 has been detected in approximately 90% of primary HCCs, which was significantly associated with high serum alpha-fetoprotein level, tumor size, microsatellite formation, thrombus, and poor overall survival of HCC patients. Compared with non-tumor tissues, higher density of methylation was identified in HCC samples. In addition, RDH16 increases the level of retinoic acid and blocks the de novo synthesis of fatty acid in HCC cells. Functional study shows that ectopic expression of RDH16 in HCC cells suppresses cell growth, clonogenicity, and cell motility. RDH16 might be a prognostic biomarker and intervention point for new therapeutic strategies in HCC.

Preoperative elevated plasma fibrinogen level predicts tumor recurrence and poor prognosis in patients with hepatocellular carcinoma.

Elevated plasma fibrinogen has been reported to be associated with poor prognosis in several cancers. The aim of present study was to investigate the prognostic value of preoperative plasma fibrinogen in hepatocellular carcinoma (HCC) patients. Data were collected retrospectively from 302 HCC patients who received hepatectomy. The association between fibrinogen and clinicopathological characteristics was evaluated. Both univariate and multivariate analyses were performed to identify prognostic factors for disease-free survival (DFS) and overall survival (OS). And accordingly, the nomograms were constructed. Elevated plasma fibrinogen (>4 g/L) was correlated with larger tumor diameter, the presence of vascular invasion, lower MELD score, higher NLR, advanced Barcelona Clinic Liver Cancer stage and poor-moderate pathological differentiation. On multivariate analysis, the elevated plasma fibrinogen was found independently associated with poor DFS (HR =1.575, P=0.024) and OS (HR =2.051, P=0.025). And the nomograms including fibrinogen were constructed to predict DFS and OS for HCC patients. Both DFS and OS in patients with plasma fibrinogen >4 g/L were significantly lower than those with fibrinogen ≤4 g/L (1-, 3-, 5-year DFS: 34.2%, 19.5% and 0.0% vs. 60.4%, 34.2% and 30.2%; 1-, 3-, 5-year OS: 83.4%, 62.7% and 48.8% vs. 95.4%, 84.3% and 75.8%, both P<0.001). Besides, subgroup analyses also showed the prognostic values of fibrinogen in HCC patients with/without cirrhosis or high AFP levels, and in those with single tumor and BCLC 0-A stage. Preoperative elevated plasma fibrinogen was an independent prognostic factor associated with poor prognosis in HCC patients receiving liver resection.

Comprehensive characterization of tumor infiltrating natural killer cells and clinical significance in hepatocellular carcinoma based on gene expression profiles

Natural Killer (NK) cells are effector lymphocytes involved in tumor immunosurveillance, however, the specific mechanism in hepatocellular carcinoma (HCC) has not been well understood. In the present study, we estimated the relative abundances of NK cells in HCC using gene expression data, and found that NK cell abundance was lower in HCC tissues than in the adjacent normal tissues. With the common HCC subclasses, we also found that three HCC subclasses had distinct abundances of NK cells. Moreover, we also found strong association between NK cell abundances and genes encoding immune checkpoint proteins, such as KLRD1, CD96, TIGIT, CD86, HAVCR2, PDCD1 (PD-1), HLA-E, CD274 (PD-L1), and CTLA4, among which, KLRD1 vs. HLA-E, CD274 vs. PDCD1, and CTLA4 vs. CD86 were three pairs of receptors and ligands. Furthermore, we investigated the clinical significance of NK cell activities in HCC, and found that the NK cell abundances were highly associated with the response to sorafinib, and higher NK cell abundances may prolong both the recurrence-free and overall survival of HCC patients. In summary, the present study not only improved our understanding of the potential tumor immune evasion mechanism of NK cells in HCC, but also proposed the potential clinical application of NK activities in HCC treatment and risk assessment.

Identification of Key Genes and Prognostic Value Analysis in Hepatocellular Carcinoma by Integrated Bioinformatics Analysis.

Emerging evidence indicates that various functional genes with altered expression are involved in the tumor progression of human cancers. This study is aimed at identifying novel key genes that may be used for hepatocellular carcinoma (HCC) diagnosis, prognosis, and targeted therapy. This study included 3 expression profiles (GSE45267, GSE74656, and GSE84402), which were obtained from the Gene Expression Omnibus (GEO). GEO2R was used to analyze the differentially expressed genes (DEGs) between HCC and normal samples. The functional and pathway enrichment analysis was performed by the Database for Annotation, Visualization and Integrated Discovery. A protein-protein interaction (PPI) network of the identified DEGs was constructed using the Search Tool for the Retrieval of Interacting Gene, and hub genes were identified. ONCOMINE and CCLE databases were used to verify the expression of the hub genes in HCC tissues and cells. Kaplan-Meier plotter was used to assess the effects of the hub genes on the overall survival of HCC patients. A total of 99 DEGs were identified from the 3 expression profiles. These DEGs were enriched with functional processes and pathways related to HCC pathogenesis. From the PPI network, 5 hub genes were identified. The expression of the 5 hub genes was all upregulated in HCC tissues and cells compared with the control tissues and cells. Kaplan-Meier survival curves indicated that high expression of cyclin-dependent kinase (CDK1), cyclin B1 (CCNB1), cyclin B2 (CCNB2), MAD2 mitotic arrest deficient-like 1 (MAD2L1), and topoisomerase IIα (TOP2A) predicted poor overall survival in HCC patients (all log-rank P < 0.01). These results revealed that the DEGs may serve as candidate key genes during HCC pathogenesis. The 5 hub genes, including CDK1, CCNB1, CCNB2, MAD2L1, and TOP2A, may serve as promising prognostic biomarkers in HCC.

Ubiquitin-conjugating enzyme E2T knockdown suppresses hepatocellular tumorigenesis via inducing cell cycle arrest and apoptosis.

BACKGROUNDHepatocellular carcinoma (HCC) is now the most common primary liver malignancy worldwide, and multiple risk factors attribute to the occurrence and development of HCC. Recently, increasing studies suggest that ubiquitin-conjugating enzyme E2T (UBE2T) serves as a promising prognostic factor in human cancers, although the molecular mechanism of UBE2T in HCC remains unclear.AIMTo investigate the clinical relevance and role of UBE2T in HCC development.METHODSUBE2T expression in HCC tissues from the TCGA database and its association with patient survival were analyzed. A lentivirus-mediated strategy was used to knock down UBE2T in HCC cells. qRT-PCR and Western blot assays were performed to check the effect of UBE2T silencing in HCC cells. Cell growth in vitro and in vivo was analyzed by multiparametric high-content screening and the xenograft tumorigenicity assay, respectively. Cell cycle distribution and apoptosis were determined by flow cytometry. The genes regulated by UBE2T were profiled by microarray assay.RESULTSUBE2T was overexpressed in HCC tissues compared with paired and non-paired normal tissues. High expression of UBE2T predicted a poor overall survival in HCC patients. In vitro, lentivirus-mediated UBE2T knockdown significantly reduced the viability of both SMMC-7721 and BEL-7404 cells. In vivo, the xenograft tumorigenesis of SMMC-7721 cells was largely attenuated by UBE2T silencing. The cell cycle was arrested at G1/S phase in SMMC-7721 and BEL-7404 cells with UBE2T knockdown. Furthermore, apoptosis was increased by UBE2T knockdown. At the molecular level, numerous genes were dysregulated after UBE2T silencing, including IL-1B, FOSL1, PTGS2, and BMP6.CONCLUSIONUBE2T plays an important role in cell cycle progression, apoptosis, and HCC development.

Upregulation of histamine receptor H1 promotes tumor progression and contributes to poor prognosis in hepatocellular carcinoma

H1 histamine receptor (H1HR) belongs to the family of rhodopsin-like G-protein-coupled receptors. Recent studies have shown that H1HR expression is increased in several types of cancer. However, its functional roles in tumor progression remain largely unknown, especially in hepatocellular carcinoma (HCC). We found that H1HR is frequently unregulated in HCC, which is significantly associated with both recurrence-free survival and overall survival in HCC patients. Functional experiments revealed that H1HR promoted both the growth and metastasis of HCC cells by inducing cell cycle progression, formation of lamellipodia, production of matrix metalloproteinase 2, and suppression of cell apoptosis. Activation of cyclic adenosine monophosphate-dependent protein kinase A was found to be involved in H1HR-mediated HCC cell growth and metastasis. In addition, we found that overexpression of H1HR was mainly due to the downregulation of miR-940 in HCC cells. Moreover, the H1HR inhibitor terfenadine significantly suppressed tumor growth and metastasis in an HCC xenograft nude mice model. Our findings demonstrate that H1HR plays a critical role in the growth and metastasis of HCC cells, which provides experimental evidence supporting H1HR as a potential drug target for the treatment of HCC.

LncRNA ID2-AS1 suppresses tumor metastasis by activating the HDAC8/ID2 pathway in hepatocellular carcinoma.

Metastasis is a core hallmark of cancer that leads to high mortality of cancer patients, especially in hepatocellular carcinoma (HCC). However, the underlying mechanisms of long noncoding RNAs (lncRNAs) in HCC metastasis remain largely unknown. We found that ID2-AS1 expression decreased in metastatic HCC cell lines and HCC tissues, and lower ID2-AS1 expression predicted reduced overall survival in HCC patients. ID2-AS1 significantly suppressed the migration, invasion and metastasis of HCC cells in vitro and in vivo. Mechanistically, ID2-AS1 regulated the transcription of its adjacent gene inhibitor of DNA binding 2 (ID2) by blocking the binding of histone deacetylase 8 (HDAC8) on the ID2 enhancer. Furthermore, ID2-AS1 and ID2 suppressed the Twist-induced epithelial-mesenchymal transition (EMT) in HCC cells. In addition, ID2 expression was also significantly decreased in HCC tissues and was positively correlated with ID2-AS1 in HCC tissues and HCC cell lines. Taken together, our findings demonstrated that ID2-AS1 regulated adjacent ID2 transcription by manipulating chromatin modification and that the newly identified ID2-AS1/ID2 axis suppressed HCC metastasis by regulating EMT processes. Our findings provide insights into the molecular mechanisms underlying the metastasis of HCC cells.

Identification of potential hub genes related to the progression and prognosis of hepatocellular carcinoma through integrated bioinformatics analysis.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths among cancer patients. Genes correlated with the progression and prognosis of HCC are critically needed to be identified. In the present study, 3 Gene Expression Omnibus (GEO) datasets (GSE46408, GSE65372 and GSE84402) were used to analyze the differentially expressed genes (DEGs) between HCC and non-tumor liver tissues. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to clarify the functional roles of DEGs. A protein-protein interaction network was established to screen the hub genes associated with HCC. The prognostic values of hub genes in HCC patients were analyzed using The Cancer Genome Atlas (TCGA) database. The expression levels of hub genes were validated based on ONCOMINE, TCGA and Human Protein Atlas (HPA) databases. Notably, 56 upregulated and 33 downregulated DEGs were markedly enriched under various GO terms and four KEGG terms. Among these DEGs, 10 hub genes with high connectivity degree were identified, including cyclin B1, cyclin A2, cyclin B2, condensin complex subunit 3, PDZ binding kinase, nucleolar and spindle-associated protein 1, aurora kinase A, ZW10 interacting kinetochore protein, protein regulator of cytokinesis 1 and kinesin family member 4A. The upregulated expression levels of these hub genes in HCC tissues were further confirmed by ONCOMINE, TCGA, and HPA databases. Additionally, the increased mRNA expression of each hub gene was related to the unfavorable disease-free survival and overall survival of HCC patients. The present study identified ten genes associated with HCC, which may help to provide candidate targets for the diagnosis and treatment of HCC.

Integrin alpha 7 correlates with poor clinical outcomes, and it regulates cell proliferation, apoptosis and stemness via PTK2-PI3K-Akt signaling pathway in hepatocellular carcinoma

This study aimed to evaluate the correlation of integrin alpha 7 (ITGA7) with clinical outcomes and its effect on cell activities as well as stemness in hepatocellular carcinoma (HCC). HCC tumor tissues and paired adjacent tissues from 90 HCC patients were obtained and ITGA7 expression was detected using immunohistochemistry assay. Cellular experiments were conducted to examine the effect of ITGA7 on cell activities, astemness via ITGA7 ShRNA transfection, and compensation experiments were further performed to test whether ITGA7 functioned via regulating PTK2-PI3K-AKT signaling pathway. ITGA7 was overexpressed in tumor tissues compared with paired adjacent tissues and its high expression was correlated with larger tumor size, vein invasion and advanced Barcelona Clinic Liver Cancer stage, and it also independently predicted worse overall survival in HCC patients. In cellular experiments, ITGA7 was upregulated in SMMC-7721, Hep G2, HuH-7 and BEL-7404 cell lines compared with normal human liver cells HL-7702. ITGA7 knockdown suppressed cell proliferation but promoted apoptosis, and it also downregulated CSCs markers (CD44, CD133 and OCT-4) as well as PTK2, PI3K and AKT expressions in SMMC-7721 and Hep G2 cell lines. ITGA7 overexpression promoted cell proliferation but inhibited apoptosis, and it also upregulated CSCs markers in HL-7702 cells. Further compensation experiments verified that ITGA7 regulated cell proliferation, apoptosis and CSCs markers via PTK2-PI3K-Akt signaling pathway. ITGA7 negatively associates with clinical outcomes in HCC patients, and it regulates cell proliferation, apoptosis and CSCs markers via PTK2-PI3K-Akt signaling pathway.

Improved clinical outcome using transarterial chemoembolization combined with radiofrequency ablation for patients in Barcelona clinic liver cancer stage A or B hepatocellular carcinoma regardless of tumor size: results of a single-center retrospective case control study

BackgroundTo determine the safety and efficacy of transarterial chemoembolization (TACE) combined with radiofrequency ablation (hereafter, TACE-RFA) in treating Barcelona Clinic Liver Cancer (BCLC) Stage A or B (hereafter, BCLC A/B) hepatocellular carcinoma (HCC) patients, and to explore the range of tumor sizes suitable for combination therapy.MethodsThis retrospective study assessed the consecutive medical records of HCC patients with BCLC A/B who received TACE-RFA or TACE from September 2009 to September 2018. Progression-free survival (PFS), overall survival (OS), therapeutic response, and complications were compared between the two groups.ResultsAmong 2447 patients who received TACE-RFA or TACE, 399 eligible patients were enrolled in our study, including 128 patients in the TACE-RFA group and 271 patients in the TACE group. Compared with the TACE group, the PFS and OS rates of 1,3,5,8 years in the TACE-RFA group were significantly better, with higher objective tumor regression rate and better disease control rate. RFA treatment did not increase the risk of death in patients with HCC, and both liver subcapsular hematoma and bile duct injury were improved by symptomatic treatment. Serum α-fetoprotein level and treatment method were important independent prognostic factors for OS, whereas albumin, hepatitis B and treatment method were important independent prognostic factors for PFS. Subgroup analysis showed that patients in the TACE-RFA group always showed better OS and PFS.ConclusionsTACE-RFA had an advantage over TACE alone in prolonging PFS and improving OS in HCC patients with BCLC A/B, and can benefit patients regardless of tumor size.

LncRNA OSER1-AS1 acts as a ceRNA to promote tumorigenesis in hepatocellular carcinoma by regulating miR-372-3p/Rab23 axis

Long non-coding RNAs (lncRNAs) are crucial regulators of tumorigenesis and progression in human cancer, including hepatocellular carcinoma (HCC). However, the role of most lncRNAs that are dysregulated in HCC remains to be elucidated. Here, we investigated the role of OSER1-AS1 in the progression of HCC. The results of database and qRT-PCR analysis demonstrated that OSER1-AS1 was highly expressed in HCC tissues and the high expression of OSER1-AS1 was closely associated with larger tumor size, advanced tumor stages, lower disease free survival and overall survival of HCC patients. OSER1-AS1 knockdown significantly inhibited the proliferation, invasion and migration of HCC cells, and induced the apoptosis. In addition, the dual luciferase reporter assay directly demonstrated that OSER1-AS1 functioned as a molecular sponge for miR-372-3p to promote Rab23 expression. Moreover, the results of immunohistochemistry and western blot analysis showed that Rab23 was highly expressed in HCC tissues, and the high expression of Rab23 was closely associated with the poor overall survival of HCC patients. Immunofluorescence assay also found the subcellular localization of Rab23 in HCC cells. Rab23 was obviously downregulated in cells that were transfected with miR-372-3p mimics. MiR-372-3p mimics significantly inhibited the proliferation and invasion of HCC cells). Rab23 restoration partially reversed miR-372-3p-induced tumor suppressive effects on HCC cells. In conclusion, we found that OSER1-AS1 acted as a ceRNA to sponge miR-372-3p, thereby positively regulating the Rab23 expression and ultimately acting as a tumor suppressor gene in HCC progression.

Identification of aberrantly expressed lncRNA and the associated TF-mRNA network in hepatocellular carcinoma.

Emerging evidence has indicated that long noncoding RNA (lncRNA) plays crucial roles in regulating hepatocellular carcinoma (HCC) progression. However, a comprehensive lncRNA-transcription factor (TF)-message RNA (mRNA) in HCC remains absent. The aim of this study was to identify aberrantly expressed lncRNAs and the associated TF-mRNA network in HCC. GSE124535 dataset was downloaded from the Gene Expression Omnibus database. Limma package in R was conducted to analyze abnormally expressed lncRNAs (differentially expressed lncRNAs [DELs]) and mRNAs (differentially expressed genes). The prognostic roles of screened DELs in HCC were evaluated at GEPIA. The expression of DELs that correlated with overall survival of HCC patients was further validated using circlncRNAnet, GEPIA, and StarBase. LncRNA-TF-mRNA potential triplets in HCC were predicted by LncMAP. After that, lncRNA-TF-mRNA networks were established using Cytoscape. A total of 20 upregulated and 17 downregulated DELs were identified in HCC tissues compared with adjacent noncancerous tissues. Six out of 20 upregulated and 6 out of 17 downregulated DELs were identified have significant impact on the overall survival of HCC patients. Results in circlncRNAnet, GEPIA, and Starbase confirmed the expression level of DELs obtained from GSE124535. Finally, the LncRNA-TF-mRNA regulatory networks for upregulated and downregulated lncRNA were established based on these analyses results. Among these lncRNAs in the network, the aberrantly expression of lncRNAs including LINC00511, RP11-290F5.1, MIR4435-2HG, and CTC-537E7.3 in HCC was first time reported to date. In the study, potential LncRNA-TF-mRNA regulatory networks were identified, which will advance our understanding concerning the progression of HCC.

STAT gene family mRNA expression and prognostic value in hepatocellular carcinoma.

BackgroundSignal transducer and activator of transcription (STAT) proteins are well-known transcription factors that play an important role in the progression of cancer. However, the association between STAT family genes and hepatocellular carcinoma (HCC) remains unclear. This study investigates the expression level, the prognostic value and the potential mechanism of STAT family genes in HCC.MethodsData from 365 HCC patients in The Cancer Genome Atlas (TCGA) database and 241 HCC patients in the Gene Expression Omnibus (GEO) database were used to investigate the diagnostic and prognostic values of STAT genes by survival analysis and nomogram. Gene set enrichment analysis (GSEA) was used to investigate the potential mechanism of the STAT genes in the development of HCC.ResultsOur results showed that STAT4/5B mRNA expression levels in HCC tissues were lower than those in normal tissues. Importantly, our results indicated that high expression of STAT5A, STAT5B and STAT6 was associated with better overall survival in HCC patients. Joint effects analysis of STAT5A, STAT5B and STAT6 suggested that the prognosis difference for any combination of genes was more significant than that for any individual gene. Then, we developed a risk score model could predict HCC prognosis and the nomogram visualized gene expression and clinical factors of probability for HCC prognosis. The ROC and calibration curves showed good performance in survival prediction in both the TCGA and the GEO databases. GSEA suggested that high expression of STAT5A, STAT5B and STAT6 were involved in immune-related biological processes, drug metabolism cytochrome P450, JAK-STAT signalling pathway, and PPAR signalling pathways.ConclusionOur data suggest that STAT5A, STAT5B and STAT6 expression may be potential prognostic markers of HCC and, in combination, have a better predictive value for HCC prognosis.

Mining featured biomarkers associated with vascular invasion in HCC by bioinformatics analysis with TCGA RNA sequencing data

This study aims to identify the feature genes associated with vascular invasion in hepatocellular carcinoma (HCC). Here, the RNA sequencing data related to vascular invasion in The Cancer Genome Atlas (TCGA) database, including 292 HCC patients with complete clinical data were included in our study as the training dataset for construction and E-TABM-36, including 41 HCC patients with complete clinical data was used as the validation dataset. Following data normalization, differentially expressed mRNA and copy number (CN) were selected between with and without vascular invasion samples. A support vector machine (SVM) classifier was constructed and validated in GSE9828 and GSE20017 datasets. Total 59 feature genes were found by the SVM classifier. Using Cox regression analysis, three clinical features, including Patholigic T, Stage and vascular invasion and 6 optimal prognostic genes, including ANO1, EPHX2, GFRA1, OLFM2, SERPINA10 and TKT were significantly correlated with prognosis. A risk score formula was developed to assess the prognostic value of 6 optimal prognostic genes, which were identified to possess the most remarkable correlation with overall survival in HCC patients. By performing in vitro experiments, we observed TKT was significantly increased, but OLFM2 was decreased in high metastatic potential HCC cell lines (SK-HEP-1 and MHCC-97 H) compared with low metastatic potential cell line Huh7 and normal human liver cell line LO2 using western blotting analysis. Knockdown of TKT in MHCC-97H or overexpression of OLFM2 in SK-HEP-1 significantly suppressed cell migration and invasion using transwell assays. Our results demonstrated that TKT and OLFM2 might be novel independent biomarkers for predicting survival based on the presence of vascular invasion in patients with HCC.

Prognostic value of interleukin-10 and tumor necrosis factor-\u03b1 polymorphisms in patients with hepatocellular carcinoma treated with transarterial chemoembolization

EnBackgroundTransarterial chemoembolization (TACE), a locoregional therapy, is widely recommended as first-line treatment for intermediate-stage hepatocellular carcinoma (HCC). Several prognostic indices have been used to predict overall survival in HCC patients undergoing the procedure.Patients and methodsA total of 73 patients with HCC, candidate for TACE attending to HCC clinic, Specialized Medical Hospital, Mansoura University, were subjected to full history taking, physical examination, laboratory profile and testing for interleukin (IL)-10 and tumor necrosis factor (TNF)-α polymorphisms. Aggressiveness index is calculated for all patients and followed-up for 4 weeks after TACE to asses response. According to IL-10 and TNF-α polymorphisms results, patients were divided into groups and compared.ResultsThe aggressiveness index is significantly higher in the TT/AT haplotype of IL-10 and GG haplotype of TNF-α in comparison with the other haplotypes. The TT/AT haplotype of IL-10 and GG haplotype of TNF-α are significantly associated with less favorable outcome after TACE, wherein 64.3 and 56.25% of patients showed residual active tumor tissue, respectively.ConclusionThe TT/AT haplotype of IL-10 and GG haplotype of TNF-α are associated with more aggressive pattern of HCC and less favorable outcome after TACE; hence, these patients must be treated as early as possible.

Comprehensive analysis of long non‑coding RNA‑messenger RNA‑microRNA co‑expression network identifies cell cycle‑related lncRNA in hepatocellular carcinoma.

Long non-coding RNAs (lncRNAs) have been shown to contribute to progression and prognosis of hepatocellular carcinoma (HCC). However, expression profiling and interaction of lncRNAs with messenger RNAs (mRNAs) and microRNAs (miRNAs) remain largely unknown in HCC. The expression profiling of lncRNAs, mRNA and miRNAs was obtained using microarray. The Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis were used to characterize potential functions of differentially expressed mRNAs. Cytoscape was applied to construct an lncRNA-miRNA-mRNA co-expression network and candidate lncRNAs were validated via quantitative PCR in 30 pairs of HCC and adjacent tumor-free tissues. In this study, 1,056 upregulated and 1,288 downregulated lncRNAs were identified, while 2,687 mRNAs and 6 miRNAs were aberrantly expressed in HCC compared with adjacent tumor-free tissues. Potential functions of differentially expressed mRNAs were demonstrated to significantly participate in modulating critical genes in the cell cycle, such as cyclin E1 and cyclin B2. After screening, 95 lncRNAs, 5 miRNAs and 36 mRNAs were recruited for construction of lncRNA-mRNA-miRNA co-expression network in the cell cycle pathway. Subsequently, the top 5 lncRNAs that potentially modulate critical genes in the cell cycle were selected as the candidates for further verification. Kaplan-Meier curves using the Cancer Genome Atlas database showed that 13 targeted mRNAs were associated with overall survival of HCC patients. Finally, three lncRNAs, including ENST00000522221, lnc-HACE1-6:1 and lnc-ICOSLG-11:1, are significantly upregulated in HCC tissues compared with adjacent tumor-free tissues. These findings suggest that lncRNAs play essential roles in the pathogenesis of HCC via regulating coding genes and miRNAs, and may be important targets for diagnosis and treatment of this disease.

SUCO as a Promising Diagnostic Biomarker of Hepatocellular Carcinoma: Integrated Analysis and Experimental Validation.

BackgroundHepatocellular carcinoma (HCC) is not frequently diagnosed until the late stage due to its concealed symptoms. Therefore, the identification of biomarkers that have effective diagnostic performance and act as potential key therapeutic targets for HCC becomes urgent.Material/MethodsComprehensive analysis of accumulated data downloaded from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) databases was used to obtain more reliable potential diagnostic biomarkers of HCC and to explore related molecular mechanisms. Meta-analysis and summary receiver operating characteristic (SROC) curve analysis were performed to evaluate the differential expression of SUCO gene in HCC and identify the capability of SUCO in distinguishing HCC-tissues from normal liver-tissues.ResultsSUCO was found to be upregulated in HCC-tissues and exhibited a favorable value in diagnosing HCC. Bioinformatics analysis showed that SUCO might play important roles in HCC progression, and was significantly related to cell cycle, cell metabolism, and proliferation.ConclusionsThis study was the first to demonstrate that SUCO was overexpressed in HCC-tissues, and that high expression of SUCO was significantly related to poor overall survival in HCC patients. SUCO might be a potential diagnostic biomarker for HCC patients, which promotes the tumorigenesis and progression of HCC.