Elevated expression of neuropilin-2 associated with unfavorable prognosis in hepatocellular carcinoma.
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ABSTRACT:
SUBMITTER: Dong X
PROVIDER: S-EPMC5546826 | biostudies-other | 2017
REPOSITORIES: biostudies-other
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Project description:BackgroundMembrane palmitoylated proteins (MPPs) are engaged in various biological processes, such as cell adhesion and cell polarity. Dysregulated MPP members have different effects on hepatocellular carcinoma (HCC) development. However, the role of MPP6 in HCC has been unknown.MethodHCC transcriptome and clinical data from different public databases were downloaded and analyzed, and the results were further validated by qRT-PCR, Western blotting and immunohistochemistry (IHC) using HCC cell lines and tissues. The association between MPP6 and prognosis, potential pathogenic mechanisms, angiogenesis, immune evasion, tumor mutation burden (TMB) and treatment response in HCC patients was analyzed by bioinformatics and IHC staining.ResultsMPP6 was significantly overexpressed in HCC, and its expression was related to T stage, pathologic stage, histologic grade and adverse prognosis in HCC patients. Gene set enrichment analysis revealed that differentially expressed genes were mainly enriched in the synthesis of genetic materials and the WNT signaling pathway. GEPIA database analysis and IHC staining suggested that MPP6 expression had a positive correlation with angiogenesis. Single-cell dataset analysis indicated that MPP6 was associated with features of the tumor microenvironment. Additional analyses discovered that MPP6 expression was inversely related to immune cell infiltration and was involved in tumor immune evasion. MPP6 expression was positively associated with TMB, and patients with high TMB had an adverse prognosis. Immunotherapy was more effective in HCC patients with low MPP6 expression, whereas those with high MPP6 expression responded better to sorafenib, gemcitabine, 5-FU, and doxorubicin.ConclusionsElevated MPP6 expression is associated with an unfavorable prognosis, angiogenesis and immune evasion in HCC. Moreover, MPP6 has the potential to be used to assess TMB and treatment response. Therefore, MPP6 might serve as a novel prognostic biomarker and therapeutic target for HCC.
| S-EPMC10189050 | biostudies-literature
Project description:This study aimed to investigate KIF18A expression in hepatocellular carcinoma (HCC) and to determine the possibility of KIF18A expression being a biomarker in HCC diagnosis or being an independent predictor of disease-free survival (DFS) and overall survival (OS) in HCC patients underwent surgical resection. KIF18AmRNA was detected in 216 cases of HCC tissues by quantitative real-time PCR (qRT-PCR) and in 20 cases of HCC tissues by semi-quantitative RT-PCR. KIF18A protein was determined in 32 cases of HCC tissues by immunohistochemistry (IHC). The survival probability was analyzed by Kaplan-Meier method, and survival curves between groups were obtained by using the log-rank test. Independent predictors associated with DFS were analyzed with Stepwise Cox proportional hazard models. High KIF18A mRNA level was detected in 154 out of 216 (71.3%) cases of HCC. The positive rate of KIF18A expression was significantly higher in liver cancer tissues than that in adjacent normal liver tissues (ANLT) from HCC patients [65.6% (21 of 32) vs. 25.0% (8 of 32), P=0.001]. The KIF18A expression level had positive relevance to the alpha-fetoprotein (AFP) (≥ 200 ng/ml), tumor size (≥ 5 cm), clinical tumor-node-metastasis (TNM) stage and portal vein tumor thrombus (PVTT) in HCC (all P <0.05). A survival analysis indicated that HCC patients with higher KIF18A expression had a significantly shorter DFS and OS after resection. A multivariate analysis suggested that KIF18A upregualtion was an independent factor for DFS [hazard risk (HR)=1.602; 95% confidence interval (CI), 1.029-2.579; P=0.031] and OS (HR=1.682; 95% CI, 1.089-2.600; P=0.019). KIF18A might be a biomarker for HCC diagnosis and an independent predictor of DFS and OS after surgical resection.
| S-EPMC4279371 | biostudies-literature
Project description:BackgroundTo identify potential key genes predicting unfavorable prognosis in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC).MethodsGene expression profiles of GSE121248, GSE62232, and GSE55092 from the GEO database were obtained and analyzed. Differentially expressed genes (DEGs) between HBV-associated HCC tissues and adjacent normal tissues were screened by the limma package and Venn diagram software. Functional assessment of DEGs was performed by Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Hub genes were selected by the protein-protein interaction (PPI) network and further validated by GSE14520 clinical data.ResultsA total of 26 up-regulated genes and 76 down-regulated genes were identified by analyzing three databases. GO and KEGG analysis demonstrated that these genes were involved in cell division, metabolism-related biological processes, the p53 pathway, and the cell cycle, among others. PPI network suggested that 14 hub DEGs (TOP2A, HMMR, DTL, CCNB1, NEK2, PBK, RACGAP1, PRC1, CDK1, RRM2, ECT2, BUB1B, ANLN, and ASPM) were most dysregulated and had potential to distinguish between HBV-associated HCC and noncancerous tissues. Further survival analysis of hub genes demonstrated that high expression of TOP2A was significantly associated with poor clinical outcomes of HBV-associated HCC.ConclusionsTOP2A might serve as a key gene for prognosis and as a therapeutic target for HBV-associated HCC.
| S-EPMC8267317 | biostudies-literature
Project description:Epithelial cells are held together by tight and adherent junctions, which are destroyed by the activation of epithelial-to-mesenchymal transition (EMT). The PLEKHA7-PDZD11 complex has been reported to be important for epithelial cell adhesion and connecting tissues. However, there is no research regarding the expression and role of PDZD11 in liver hepatocellular carcinoma (LIHC) progression. Here, we analyzed PDZD11 mRNA expression and its clinical results in LIHC patient RNA sequencing data based on different open databases. Furthermore, we examined differences in PDZD11 expression in LIHC tissues and cell lines using western blotting and real-time qPCR. These results are the first to report that the mRNA and protein levels of PDZD11 are significantly overexpressed in LIHC. Moreover, high expression of PDZD11 was correlated with poor overall survival in patients with LIHC. Gene regulatory network analysis suggested that PDZD11 is mainly involved in copper ion homeostasis, proteasome, and oxidative phosphorylation pathways. Interestingly, we found that PDZD11 levels were positively correlated with the abundance of immune infiltrates. In particular, higher infiltration levels of CD4+ T cells and macrophage subsets significantly affected LIHC patient prognosis. Taken together, these results demonstrate that PDZD11 could be a potential diagnostic and prognostic biomarker in LIHC.
| S-EPMC8176286 | biostudies-literature
Project description:Cyclin F, capable of forming Skp1-Cul1-F-box protein ubiquitin ligase complex, is implicated in controlling centrosome duplication and preventing genome instability. Cyclin F oscillates during cell cycle with a similar pattern to cyclin A. However, its expression and significance in cancer remain obscure. In this study, we showed that cyclin F was noticeably decreased in 16 pairs of tissue samples of hepatocellular carcinoma (HCC) compared to paracarcinoma tissues, at both mRNA and protein levels. Immunohistochemical staining data revealed that in 71.8% (176/245) of HCC cases, cyclin F expression in tumor tissue was much lower than that in nontumorous tissue. Low cyclin F expression, defined by receiver operating characteristic curve analysis, was present in 69.0% of HCC patients. Low expression of cyclin F was significantly correlated with tumor size, clinical stage, serum alpha-fetoprotein level and tumor multiplicity. Further study showed that cyclin F expression was reversely associated with tumor differentiation in HCC. Kaplan-Meier analysis indicated that low cyclin F expression was related to poor overall survival and recurrence-free survival. The prognostic impact of cyclin F was further confirmed by stratified survival analysis. Importantly, multivariate analysis revealed that low cyclin F expression was an independent poor prognostic marker for overall survival. We conclude that cyclin F is downregulated in HCC and is a promising prognostic marker for patients suffering from this deadly disease.
| S-EPMC7657186 | biostudies-literature
Project description:SIRT3, a mitochondrial sirtuin belonging to nicotinamide adenine nucleotide (NAD) dependent deacetylases, is implicated in metabolism, longevity and carcinogenesis. SIRT3 expression and its significance in hepatocellular carcinoma (HCC) remain largely unclear. In this study, we demonstrated that SIRT3 expression in HCC tissue was much lower than that in paracarcinoma tissue, at both mRNA and protein levels. The cutoff value for low SIRT3 expression in HCC was defined according to receiver operating characteristic curve (ROC) analysis. As disclosed by immunohistochemistry (IHC) results, low SIRT3 expression was present in 67.3% (167/248) of HCC cases. Furthermore, low expression of SIRT3 was significantly correlated to differentiation (P?=?0.013), clinical stage (P?=?0.005), serum AFP level (P<0.01), tumor multiplicity (P?=?0.026) and relapse (P?=?0.028). Moreover, Kaplan-Meier analysis indicated that low SIRT3 expression associated with unfavorable overall survival (P<0.01) and recurrence-free survival (P?=?0.004). The prognostic impact of SIRT3 was further confirmed by stratified survival analysis. Importantly, multivariate analysis revealed that low SIRT3 expression was an independent poor prognostic marker for overall survival (Hazard Ratio (HR) 0.555, 95% confidence interval (95% CI) 0.344-0.897, P?=?0.016). Collectively, we conclude that SIRT3 is decreased in HCC and is a novel unfavorable marker for prognosis of patients with this fatal disease.
| S-EPMC3522714 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDAC) is the most lethal cancer in humans, with a 5-year survival rate of <5%. Recently, glypican-1 (GPC1)-expressing circulating exosomes were found to be a promising diagnostic tool for PDAC. However, the aberrant expression of GPC1 has not been systematically evaluated in large-scale clinical samples of PDAC. Here, we performed a comprehensive analysis of GPC1 mRNA and protein expression features. Included in this study were 178 PDAC patients from the cancer genome atlas (TCGA) and 186 subjects whose tissues were used in immunohistochemical staining assays. We demonstrated that GPC1 mRNA was silenced in normal pancreata; however, it was re-expressed in PDAC tissues probably because of the promoter hypomethylation. The GPC1 protein was barely expressed in the normal and adjacent noncancerous pancreata. In tumor tissues, 59.7% (111/186) of the detected samples showed positive expression. Notably, GPC1 was elevated in 63.6% (34/55) of early stage cases. High levels of GPC1 were associated with poorer differentiation and larger tumor diameters. Kaplan-Meier analysis showed a significant difference in overall survival between the groups categorized by GPC1 expression (P = 0.0028). Multivariate analyses indicated that GPC1 was a significant risk factor for poor overall survival with a 1.82-fold increase in the hazard ratio (P = 0.0022). In conclusion, during pancreatic tumorigenesis, GPC1 was ectopically expressed and served as an independent poor prognostic factor. Our findings highlighted the alluring prospect of GPC1 as an early diagnostic and prognostic marker as well as a therapeutic target for PDAC.
| S-EPMC5463070 | biostudies-literature
Project description:BackgroundThe oncogenic role of excision repair cross-complementation group 6-like (ERCC6L) has been revealed in several cancers recently, but little is known about its expression and function in hepatocellular carcinoma (HCC).MethodsUtilizing public data from Human Protein Atlas (HPA) and The Cancer Genome Atlas (TCGA) databases, ERCC6L dysregulation in HCC and its clinical significance were determined by t-test and Chi-square test. Comprehensive survival analyses (such as nomogram, Cox regression model and Kaplan-Meier analysis) were performed to assess prognostic value of ERCC6L for HCC patients. Integrated bioinformatics analyses [including copy number alterations (CNA), DNA methylation, miRNA prediction and gene set enrichment analysis (GSEA)] were conducted to explore the mechanisms and biological roles underlying ERCC6L dysregulation in HCC.ResultsERCC6L upregulation was identified in HCC tissues compared to normal controls (P<0.05). In addition, overexpression of ERCC6L not only correlated with elevated alpha fetoprotein (AFP), vascular invasion (VI), and advanced histologic grade and TNM stage, but also had an independent prognostic value for the poorer overall survival (OS) and recurrence-free survival (RFS) of HCC patients (all P<0.05). Besides, nomogram integrating ERCC6L expression and TNM stage showed superior prognostic ability than that of TNM stage (P<0.05). Moreover, ERCC6L promoter hypomethylation and miR-5589 downregulation in HCC might result in ERCC6L overexpression (all P<0.05). Furthermore, eight biological pathways (including the DNA replication, cell cycle and p53 pathways) related to ERCC6L upregulation in HCC were found to be enriched by GSEA, and ERCC6L upregulation was positively correlated with PLK1 (polo-like kinase 1) expression and TP53 mutation in HCC, which preliminarily shed light on the roles of ERCC6L in HCC.ConclusionsERCC6L may serve as a promising prognostic indicator and therapeutic target for HCC patients.
| S-EPMC7657825 | biostudies-literature
Project description:BackgroundHepatectomy generally offers the best chance of long-term survival for patients with hepatocellular carcinoma (HCC). Many studies have shown that hepatectomy accelerates tumor metastasis, but the mechanism remains unclear.MethodsAn orthotopic nude mice model with palliative HCC hepatectomy was performed in this study. Metastasis-related genes in tumor following resection were screened; HCC invasion, metastasis, and some molecular alterations were examined in vivo and in vitro. Clinical significance of key gene mRNA expression was also analyzed.ResultsMetastasis suppressor 1 (MTSS1) located in the central position of gene function net of residual HCC. MTSS1 was up-regulated in residual tumor after palliative resection. In hepatitis B-related HCC patients undergone palliative hepatectomy, those with higher MTSS1 mRNA expression accompanied by activation of matrix metalloproteinase 2 (MMP2) in residual HCC, had earlier residual HCC detection after hepatectomy and poorer survival when compared to those with lower MTSS1. In different cell lines, the levels of MTSS1 mRNA increased in parallel with metastatic potential. MTSS1 down regulation via siRNA decreased MMP2 activity, reduced invasive potentials of HCC by 28.9 % in vitro, and averted the deteriorated lung metastatic extent in vivo.ConclusionsThe poor prognosis of hepatitis B-related HCC patients following palliative hepatectomy associates with elevated MTSS1 mRNA expression; therefore, MTSS1 may provide a new research field for HCC diagnosis and treatment.
| S-EPMC4881066 | biostudies-literature
Project description:BackgroundExtensive evidence links Clonorchis sinensis (C. sinensis) to cholangiocarcinoma; however, its association with hepatocellular carcinoma (HCC) is less acknowledged, and the underlying mechanism remains unclear. This study was designed to investigate the association between C. sinensis infection and HCC and reveal the relationship between C. sinensis infection and cancer stemness.MethodsA comprehensive analysis of 839 HCC patients categorized into C. sinensis (-) HCC and C. sinensis (+) HCC groups was conducted. Chi-square and Mann-Whitney U tests were used to assess the association between C. sinensis infection and clinical factors. Kaplan-Meier and Cox regression analyses were used to evaluate survival outcomes. Immunohistochemistry was used to determine CK19 and EpCAM expression in HCC specimens.ResultsCompared to C. sinensis (-) HCC patients, C. sinensis (+) HCC patients exhibited advanced Barcelona Clinic Liver Cancer (BCLC) stage, higher male prevalence and more liver cirrhosis as well as elevated alpha-fetoprotein (AFP), carbohydrate antigen 19-9 (CA19-9), eosinophil, complement 3 (C3), and complement 4 (C4) values. C. sinensis infection correlated with shorter overall survival (OS) (p < 0.05) and recurrence-free survival (RFS) (p < 0.05). Furthermore, Cox multivariate analysis revealed that C. sinensis infection was an independent prognostic factor for OS in HCC patients. Importantly, C. sinensis infection upregulated the expression of HCC cancer stem cell markers CK19 and EpCAM.ConclusionHCC patients with C. sinensis infection exhibit a poor prognosis following hepatectomy. Moreover, C. sinensis infection promotes the acquisition of cancer stem cell-like characteristics, consequently accelerating the malignant progression of HCC.Author summaryClonorchis sinensis (C. sinensis) is a prominent food-borne parasite prevalent in regions such as China, particularly in Guangxi. C. sinensis has been associated with various hepatobiliary system injuries, encompassing inflammation, periductal fibrosis, cholangiocarcinoma and even hepatocellular carcinoma (HCC). A substantial body of evidence links C. sinensis to cholangiocarcinoma, However, the connection between C. sinensis and HCC and the intricate mechanisms underlying its contribution to HCC development remain incompletely elucidated. Our study demonstrates clear clinicopathological associations between C. sinensis and HCC, such as gender, BCLC stage, liver cirrhosis, MVI, AFP, CA19-9, circulating eosinophils and complements. Furthermore, we found that the co-occurrence of C. sinensis exhibited a significant association with shorter OS and RFS in patients diagnosed with HCC. A major finding was that C. sinensis infection promotes the acquisition of cancer stem cell-like characteristics, consequently accelerating the malignant progression of HCC. Our results provide a more comprehensive comprehension of the interplay between C. sinensis and HCC, shedding fresh light on the carcinogenic potential of C. sinensis.
| S-EPMC10824460 | biostudies-literature