Higher expression of A-kinase anchoring-protein 1 predicts poor prognosis in human hepatocellular carcinoma.
Ontology highlight
ABSTRACT:
SUBMITTER: Yu J
PROVIDER: S-EPMC6006472 | biostudies-literature | 2018 Jul
REPOSITORIES: biostudies-literature
Publications
Higher expression of A-kinase anchoring-protein 1 predicts poor prognosis in human hepatocellular carcinoma.
Yu Jian J Zhang Yu Y Zhou Dongxun D Wu Jun J Luo Rong R
Oncology letters 20180510 1
A-kinase anchoring protein 1 (AKAP1) plays important regulatory roles in the regulation of mitochondrial function, oxidative metabolism, and cell survival. However, the expression pattern and prognostic value of AKAP1 in hepatocellular carcinoma (HCC) remains unclear. AKAP1 expression levels in tumor and matched non-tumor tissues were evaluated using reverse transcription-quantitative polymerase chain reaction and immunohistochemical staining. Kaplan-Meier and Cox regression analyses were used t ...[more]
Similar Datasets
Project description:Background - Hepatocellular carcinomas (HCCs) are heterogeneous tumors with respect to etiology, cell of origin and biology. The course of the disease is unpredictable and is in part dependent on the tumor microenvironment. One of the microenvironmental factors is hypoxia, which is known to promote aggressiveness in other malignant tumors. We hypothesized that certain regions in HCC exist with chronic hypoxia and a characteristic gene expression pattern. Moreover, during the development of HCC there is an important contribution of this chronic hypoxia on prognosis via this gene expression. Until now, most research has been performed in acute hypoxic models (< 24 hours). Methods – Human hepatoblastoma cells HepG2 were cultured in either normoxic (20% O2) or hypoxic (2% O2) conditions for 72 hrs, the time it takes to adapt to chronic hypoxia. After 3 days the cells were harvested and analyzed by microarray technology. The highly significant differentially expressed genes were selected and used to assess the clinical value of our in vitro chronic hypoxia gene signature in four published patient studies. Three of these independent microarray studies on HCC patients were used as training sets to determine a minimal prognostic gene set and one study was used for validation. Gene expression analysis and correlation with clinical outcome was assessed with the bioinfomatic method of Goeman et al (). Results – In the HepG2 cells, 3592 genes were differentially expressed in cells cultured at 2% oxygen for 72 hrs. Out of these, 265 showed a high significant change (2-fold change and p=0.0001). The level of gene expression after 72 hrs was different from the acute hypoxic response (during the first 24 hours) and represented chronicity. Using computational methods we identified 7 out of the 265 highly significant genes that showed correlation with prognosis in all three different training sets and this was independently validated in a 4th dataset. With our approach we could include the largest number of HCC patients in one single study. Conclusion – We identified a 7-gene signature, which is associated with chronic hypoxia and predicts prognosis in patients with HCC. In the future this signature could be used as a diagnostic tool. In addition, chronic hypoxia gene expression information can be used in the search for new therapeutic targets. Two conditions were compared and each sample has a biological replicate. Samples are hybridized in dye-swap, resulting in 4 hybridizations.
2010-07-20 | E-GEOD-15366 | biostudies-arrayexpress
Project description:Background - Hepatocellular carcinomas (HCCs) are heterogeneous tumors with respect to etiology, cell of origin and biology. The course of the disease is unpredictable and is in part dependent on the tumor microenvironment. One of the microenvironmental factors is hypoxia, which is known to promote aggressiveness in other malignant tumors. We hypothesized that certain regions in HCC exist with chronic hypoxia and a characteristic gene expression pattern. Moreover, during the development of HCC there is an important contribution of this chronic hypoxia on prognosis via this gene expression. Until now, most research has been performed in acute hypoxic models (< 24 hours). Methods – Human hepatoblastoma cells HepG2 were cultured in either normoxic (20% O2) or hypoxic (2% O2) conditions for 72 hrs, the time it takes to adapt to chronic hypoxia. After 3 days the cells were harvested and analyzed by microarray technology. The highly significant differentially expressed genes were selected and used to assess the clinical value of our in vitro chronic hypoxia gene signature in four published patient studies. Three of these independent microarray studies on HCC patients were used as training sets to determine a minimal prognostic gene set and one study was used for validation. Gene expression analysis and correlation with clinical outcome was assessed with the bioinfomatic method of Goeman et al (). Results – In the HepG2 cells, 3592 genes were differentially expressed in cells cultured at 2% oxygen for 72 hrs. Out of these, 265 showed a high significant change (2-fold change and p=0.0001). The level of gene expression after 72 hrs was different from the acute hypoxic response (during the first 24 hours) and represented chronicity. Using computational methods we identified 7 out of the 265 highly significant genes that showed correlation with prognosis in all three different training sets and this was independently validated in a 4th dataset. With our approach we could include the largest number of HCC patients in one single study. Conclusion – We identified a 7-gene signature, which is associated with chronic hypoxia and predicts prognosis in patients with HCC. In the future this signature could be used as a diagnostic tool. In addition, chronic hypoxia gene expression information can be used in the search for new therapeutic targets.
2010-07-20 | GSE15366 | GEO
Project description:Previous cDNA microarray experiments revealed that the ATP-dependent DNA helicase Q4 (RECQL4) gene is overexpressed in hepatocellular carcinoma (HCC) tissues. However, the exact role of RECQL4 in HCC remains unknown. The present study aimed to investigate RECQL4 expression in HCC and to analyze the potential clinical implications of RECQL4 expression in HCC patients. The expression of RECQL4 mRNA was assessed in 205 samples of HCC tissues by reverse transcription-quantitative polymerase chain reaction. The results demonstrated that the expression of RECQL4 mRNA in HCC tissues was significantly higher compared with adjacent normal liver tissues (P<0.001). The level of RECQL4 mRNA expression was associated with high a-fetoprotein (AFP) levels (>100 ng/ml), tumor size (>6 cm), and Barcelona Clinic Liver Cancer stage (all P<0.05). Kaplan-Meier survival analysis indicated that HCC patients with higher levels of RECQL4 expression exhibited significantly shorter disease-free survival (DFS) and overall survival (OS) times compared with those with low levels of expression. Multivariate survival analysis revealed that high RECQL4 expression was a significant independent predictor for DFS [HR, 1.635; 95% confidence interval (CI), 1.062-2.515; P=0.025] and OS (HR, 1.618; 95% CI, 1.050-2.493; P=0.029) of HCC patients. These data indicated that RECQL4 might be a novel diagnostic and prognostic biomarker for HCC patients.
| S-EPMC5835851 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is one of the most commonly cancers with poor prognosis and drug response. Identifying accurate therapeutic targets would facilitate precision treatment and prolong survival for HCC. In this study, we analyzed liver hepatocellular carcinoma (LIHC) RNA sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA), and identified PARD3 as one of the most significantly differentially expressed genes (DEGs). Then, we investigated the relationship between PARD3 and outcomes of HCC, and assessed predictive capacity. Moreover, we performed functional enrichment and immune infiltration analysis to evaluate functional networks related to PARD3 in HCC and explore its role in tumor immunity. PARD3 expression levels in 371 HCC tissues were dramatically higher than those in 50 paired adjacent liver tissues (p < 0.001). High PARD3 expression was associated with poor clinicopathologic feathers, such as advanced pathologic stage (p = 0.002), vascular invasion (p = 0.012) and TP53 mutation (p = 0.009). Elevated PARD3 expression also correlated with lower overall survival (OS, HR = 2.08, 95% CI = 1.45-2.98, p < 0.001) and disease-specific survival (DSS, HR = 2.00, 95% CI = 1.27-3.16, p = 0.003). 242 up-regulated and 71 down-regulated genes showed significant association with PARD3 expression, which were involved in genomic instability, response to metal ions, and metabolisms. PARD3 is involved in diverse immune infiltration levels in HCC, especially negatively related to dendritic cells (DCs), cytotoxic cells, and plasmacytoid dendritic cells (pDCs). Altogether, PARD3 could be a potential prognostic biomarker and therapeutic target of HCC.
| S-EPMC8154901 | biostudies-literature
Project description:Human cells exposed to environmental or endogenous carcinogens can develop DNA damage. This DNA damage may contribute to a susceptibility to cancer; therefore, it is important to repair these defects. The nucleotide excision repair pathway (NER) is a versatile DNA repair pathway that eliminates a wide variety of helix-distorting base lesions induced by environmental or endogenous carcinogenic sources. The excision repair cross-complementation group 5 (ERCC5) gene is a central component of NER. Ectopic expression of ERCC5 has been linked to different types of cancers, including hepatocellular carcinoma (HCC). However, previous reports, mainly based on mRNA level and the role of ERCC5 in cancer, remain conflicting and unclear. In this study, we examined 104 cases of HCC for immunohistochemistry to explore the role of ERCC5 protein in HCC. We found the expression of ERCC5 protein was significantly increased in tumor tissues compared to paracancerous ones (P<0.01). The percentage of positive staining of ERCC5 in tumor tissues was 28.8% (30/104), while only 4.8% (5/104) in paracancerous tissues. Patients with low ERCC5 expression levels had a better overall survival rate and remained disease-free longer (both P<0.01). In addition, univariate and multivariate analysis showed a high expression of ERCC5 protein and large tumor size predict a poor prognosis for patients with HCC (P<0.05).
| S-EPMC6962895 | biostudies-literature
Project description:BackgroundHepatocellular carcinoma (HCC) is the second-most lethal cancer worldwide with a complex pathogenesis. RuvB-like 2 (RUVBL2) was previously found to contribute to hepatocarcinogenesis. However, its expression, regulation and clinical significance have not been systematically evaluated in a large number of clinical samples.MethodsHere, we performed a comprehensive analysis of RUVBL2 based on multiple datasets from 371 liver cancer patients of The Cancer Genome Atlas (TCGA) and on immunohistochemical staining in 153 subjects. In addition, the aberrant signaling pathways caused by RUVBL2 overexpression were investigated.ResultsWe demonstrated that promoter hypomethylation, copy number gain, MYC amplification and CTNNB1 mutation were all responsible for RUVBL2 overexpression in HCC. High levels of RUVBL2 mRNA were associated with shorter recurrence-free survival time (RFS) but not overall survival time (OS). Furthermore, RUVBL2 protein was overexpressed in the nucleus and cytoplasm of HCC samples. Univariate and multivariate survival analyses showed that strong nuclear and cytoplasmic staining of RUVBL2 independently predicted worse OS and RFS with a 2.03-fold and a 1.71-fold increase in the hazard ratio, respectively. High levels of RUVBL2 promoted carcinogenesis through the heat shock protein 90 (HSP90)-Cell Division Cycle 37 (CDC37), AKT serine/threonine kinase (AKT) and mitogen-activated protein kinase (ERK/MAPK) pathways.ConclusionThe deregulation of RUVBL2 in HCC is influenced at the genomic, epigenetic and transcriptional levels. Our findings highlight the potential roles of RUVBL2 as a promising prognostic marker as well as a therapeutic target for HCC.
| S-EPMC6764127 | biostudies-literature
Project description:The present study aimed to investigate anaplastic lymphoma kinase (ALK) status in hepatocellular carcinoma (HCC) and to evaluate whether abnormalities in expression were associated with patient prognosis. ALK status was investigated using immunohistochemistry (IHC), reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and fluorescence in situ hybridization (FISH) assays in 342 HCC patients. In addition, rapid amplification of complementary DNA ends-coupled PCR sequencing was performed, in order to confirm the presence of ALK abnormalities in patients exhibiting ALK messenger RNA (mRNA) overexpression. The correlation between ALK expression and the clinicopathological features and prognosis of the HCC patients was statistically analyzed. The results of the present study revealed overexpression of ALK protein and mRNA; furthermore, ALK gene copy number gains were observed via IHC (44.7%; 153/342), RT-qPCR (47.4%; 162/342) and FISH (32.7%; 112/342) analyses, although ALK rearrangement or mutation was not demonstrated in the results of any of these assays. ALK protein expression levels were significantly associated with hepatitis C virus (HCV) status (P<0.001) and the presence of micrometastases (P=0.011). Within the entire patient cohort, ALK expression was associated with poor progression-free survival (PFS; P=0.041). Subsequent analysis in patient subgroups that demonstrated hepatitis B surface antigen positivity, HCV negativity, stage III-IV disease, recurrence and micrometastasis positivity revealed that overall survival (OS) and PFS were significantly reduced in those patients exhibiting ALK expression compared with those patients who were negative for ALK expression. Multivariate analysis revealed that ALK expression was an independent risk factor for OS (P=0.042) and PFS (P=0.033), particularly for patients with stage III-IV tumors. Thus, ALK may serve as a novel indicator for the metastatic behavior and prognosis of HCC.
| S-EPMC4727030 | biostudies-literature
Project description:Transforming growth factor beta (TGF-?) promotes the pathogenesis of hepatocellular carcinoma (HCC). We evaluated the associations between TGF-?1 expression and clinicopathological parameters in HCC patients from The Cancer Genome Atlas (TCGA), as well as the prognostic power of TGF-?1 expression. Eligible studies were retrieved from several databases, and effects (hazard ratios (HRs) with 95% confidence intervals (CIs)) for overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS), metastasis-free survival (MFS), and progression-free survival (PFS) were pooled to assess the prognostic ability of TGF-?1 expression in HCC patients. Twelve qualified articles and our TCGA data comprising 2,021 HCC patients were incorporated. In the TCGA analysis, HCC patients with higher TGF-?1 expression presented a shorter OS than those with lower TGF-?1 expression (HR = 1.42, p < 0.05). In the meta-analysis, univariate analyses showed that HCC patients with higher TGF-?1 expression had a shorter OS (pooling HR = 1.71, p < 0.01) and DFS/RFS/MFS/PFS (pooling HR = 1.60, p < 0.01) than those with lower TGF-?1 expression. In conclusion, our results suggested that high TGF-?1 expression promotes a poor prognosis in HCC patients.
| S-EPMC5470976 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is one of the most lethal cancer types, and chronic infection with Hepatitis B Virus (HBV) is identified as the strongest risk factor for HCC. Transmembrane Protein 173 (TMEM173) is a pattern recognition receptor which functions as a major regulator of the innate immune response to viral and bacterial infections. However, the prognostic value of TMEM173 in HCC remains elusive. Thus, we aimed to evaluate the potential prognostic significance of TMEM173 expression in HCC patients following curative resection. Immunohistochemistry was used to detect TMEM173 expression in 96 HCC patients. We found that TMEM173 protein expression was remarkably decreased in tumor tissues compared to non-tumor tissues, and that TMEM173 staining intensity was inversely correlated with tumor size, tumor invasion TNM stage and overall survival (OS) in HCC patients. Multivariate analysis supported TMEM173 as an independent prognostic factor, and identified that combining TMEM173 expression with TNM stage showed better prognostic efficiency for OS in HCC patients. In summary, TMEM173 was discovered having an independent prognostic value and may serve as a potential immunotherapeutic target for HCC.
| S-EPMC5096716 | biostudies-literature
Project description:BackgroundNDC1 was identified to be a tumor-promoting factor in non-small cell lung cancer and cervical cancer. However, no report had clarified the relationship between NDC1 and hepatocellular carcinoma (HCC). In this paper, we explored the expression and potential functions of NDC1 in HCC for the first time through the rational application of bioinformatics and relevant basic experiments.MethodsNDC1-related expression profiles and clinical data of HCC patients were collected from The Cancer Genome Atlas (TCGA) database, which were verified via quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. Univariate and multivariate Cox regression analyses were used to identify NDC1 as an independent factor for HCC prognosis, and NDC1-related signaling pathways were determined by gene set enrichment analysis (GSEA). Furthermore, we deeply probed the potential links of NDC1 to immunity and immune response. Finally, the bioeffects and underlying mechanisms of ectopic NDC1 overexpression and depletion were determined in HepG2 cells by immunoblotting, flow cytometry, Cell-Counting-Kit-8 (CCK-8), and EDU (5-Ethynyl-2'-deoxyuridine).ResultsUp-regulated expression of NDC1 was detected by means of the TCGA database, which was consistent with the results obtained from further qRT-PCR, immunohistochemistry and the CPTAC database. Kaplan-Meier (K-M) survival analysis revealed a worse prognosis in HCC patients with high NDC1 expression. Besides, NDC1 was certified to be closely linked to tumor histologic grade, clinical stage and T stage. Moreover, univariate and multivariate Cox regression analyses defined NDC1 as an independent element for HCC prognosis. NDC1-related signaling pathways, utilizing GSEA analysis, were subsequently found out. What's more, NDC1 expression was detected to be enormously associated with microsatellite instability (MSI), immune cell infiltration, immune checkpoint molecules and immune cell pathways. As for immunotherapy, we discovered that different risk groups tended to have different immune checkpoint inhibitor responses, which indicated crucial implication value of NDC1 for HCC immunotherapy. More interestingly, we observed that the overexpression of NDC1 could promote the migration and invasion of HCC cells.ConclusionsOur article demonstrated that NDC1 might serve as a valuable predictor in the prognosis and immunotherapy of HCC. NDC1 played an oncogenic role in HCC.
| S-EPMC10007937 | biostudies-literature