Analysis of clinicopathologic and imaging features of dual-phenotype hepatocellular carcinoma.

Dual-phenotype hepatocellular carcinoma (DPHCC) is a new subtype of hepatocellular carcinoma (HCC). This study aimed to investigate the relationship between the computerized tomography scan (CT) imaging and clinicopathologic features of DPHCC. The CT imaging and clinicopathologic data of 97 HCC cases who underwent radical resection were collected retrospectively. The CT imaging feature was evaluated by the ratio of the average CT value of tumor to liver (TLR) in the plain scan, arterial, portal vein and delayed phases. The association between CT imaging and clinicopathologic features was analyzed using the t-test or chi-square test. Univariate and multivariate recurrence-free survival (RFS) analysis and overall survival (OS) were performed. The positive rates of cytokeratin 7 (CK7) and CK19 were 35.1% and 20.6% respectively. The positive rate of CK19 was significantly higher in cases with age < 47 years (P = 0.005), tumor diameter > 4 cm (P = 0.016) or AFP ≥ 400 ng/ml (P = 0.007). The TLR in the portal vein phase was significantly lower in CK19 positive group (P = 0.024). The recurrence risk was significantly higher in cases with CK19 positive (HR: 2.17, 95% CI 1.16 to 4.04, P = 0.013), tumor diameter > 4 cm (HR: 2.05, 95% CI 1.11 to 3.78, P = 0.019), AFP ≥ 400 ng/ml (HR: 2.50, 95% CI 1.37 to 4.54, P = 0.002) or CA199 ≥ 37 U/ml (HR: 2.23, 95% CI 1.12 to 4.42, P = 0.020). However, imaging features, pathological subtype, CK7 or CK19 expression were not significantly related to HCC OS in the univariate and multivariate analysis (all P > 0.05). The expression of CK19 may be associated with the enhancement feature of the portal vein phase CT image, and CK19 positive may suggest a worse RFS.

Prognostic value of geriatric nutritional risk index and prognostic nutritional index in hepatocellular carcinoma.

BACKGROUND: The geriatric nutritional risk index (GNRI) and prognostic nutritional index (PNI) are considered prognostic factors for several cancers. This study aimed to investigate the relationship between the GNRI and PNI for survival outcomes in patients with hepatocellular carcinoma (HCC). METHODS: We retrospectively analyzed 1666 patients with HCC who underwent hepatectomy. Restricted cubic spline regression was used to analyze the relationship between the GNRI and PNI for recurrence and mortality. Cox proportional hazards regression analysis was used to evaluate the risk factors associated with overall survival (OS) and recurrence-free survival (RFS). Interaction analysis was performed to investigate the comprehensive effects of the GNRI, PNI, and subgroup parameters on the prognosis of patients with HCC. RESULTS: The risks of death and recurrence decreased rapidly and gradually stabilized as the GNRI and PNI scores increased. Patients with lower GNRI and PNI scores had significantly shorter OS and RFS rates than those with higher scores. Multivariate analysis showed that high GNRI [HR and 95%CI = 0.77 (0.70-0.85), P < 0.001] and PNI [HR and 95%CI = 0.77 (0.70-0.86), P < 0.001] scores were associated with decreased mortality risk. This trend was maintained by confounding variables in adjusted models despite partial interactions with clinical factors. The combined GNRI and PNI analysis showed that HCC patients with high GNRI and PNI had longer OS and RFS. CONCLUSIONS: The GNRI and PNI showed good survival predictions in patients with HCC. Combining the GNRI with PNI may help predict the prognosis of patients (age>18 years) with HCC after hepatectomy.

Outer dynein arm docking complex subunit 2 polymorphism rs7893462 modulates hepatocellular carcinoma susceptibility and can serve as an overall survival biomarker for hepatitis B virus-related hepatocellular carcinoma after hepatectomy: a cohort study with a long-term follow-up.

BACKGROUND: Genetic variants of outer dynein arm docking complex subunit 2 (ODAD2) have been reported to be closely associated with primary ciliary dyskinesia and colorectal cancer in previous studies, but the association of genetic variants of ODAD2 with hepatocellular carcinoma (HCC) has not been reported. METHODS: We enrolled 80 healthy subjects and 468 Guangxi hepatitis B virus (HBV)-related HCC patients in this study. A case-control study method was used to explore the association of different ODAD2-rs7893462 genotypes with hepatocarcinogenesis. A comprehensive survival analysis was used to explore the association of rs7893462 with the prognosis of HBV-related HCC in Guangxi. RESULTS: Through a case-control study, we observed that patients carrying the G allele of rs7893462 had a markedly increased susceptibility to hepatocarcinogenesis (odds ratio = 1.712, 95% confidence interval = 1.032-2.839, P = 0.037). We found that there were significant prognosis differences among three different genotypes of rs7893462. Nomogram analysis suggested that the contribution of rs7893462 polymorphisms to the prognosis of HBV-related HCC was second only to the BCLC stage. Stratified survival analysis suggested that the AG genotype of rs7893462 was an independent prognostic risk factor for HBV-related HCC. Joint effect survival analysis also observed that the AG genotype of rs7893462 combined with clinical parameters could significantly identify HBV-related HCC patients with different prognostic outcomes more accurately, and the AG genotype was also observed to be independent of clinical factors in HBV-related HCC survival. CONCLUSION: The ODAD2-rs7893462 polymorphisms can be used as an independent prognostic indicator of HBV-related HCC overall survival and are significantly associated with susceptibility to hepatocarcinogenesis.

A pan-cancer analysis of the expression and prognostic significance of PDRG1.

Background: PDRG1 are involved in various physiological regulations of cells, include cell proliferation, growth, apoptosis and cell cycle regulation, but their roles in cancer have not been clearly studied. Methods: Firstly, we evaluated the expression and prognostic significance of PDRG1 using a pan-cancer analysis of The Cancer Genome Atlas (TCGA) and Genotypic Tissue Expression (GTEx) databases. Secondly, correlations between PDRG1 and pan-cancer immune cells, m6A methylation, tumor mutation burden (TMB), and microsatellite instability (MSI) were investigated. Finally, we explored the relationship between PDRG1 expression and clinical stage in hepatocellular carcinoma (HCC). Results: We found that PDRG1 was significantly overexpressed in bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), cholangiocarcinoma (CHOL), liver hepatocellular carcinoma (LIHC), and other tumor tissues and was associated with prognosis. In addition, PDRG1 was closely associated with pan-cancer immune cells, m6A methylation, TMB, and MSI expression. The expression of PDRG1 in HCC was correlated with clinical stage, and western blot assay confirmed that PDRG1 was significantly overexpressed in HCC tissues. Conclusions: PDRG1 may be an important pan-cancer molecular biomarker for diagnosis and prognosis, and our results may provide a theoretical basis for its future clinical application in cancer diagnosis, treatment, and prognosis, and have been preliminarily validated in HCC.

Recurrence of Early Hepatocellular Carcinoma after Surgery May Be Related to Intestinal Oxidative Stress and the Development of a Predictive Model.

Background: Early stage hepatocellular carcinoma (HCC) has a high recurrence rate after surgery and lacks reliable predictive tools. We explored the potential of combining enhanced CT with gut microbiome to develop a predictive model for recurrence after early HCC surgery. Methods: A total of 112 patients with early HCC who underwent hepatectomy from September 2018 to December 2020 were included in this study, and the machine learning method was divided into a training group (N = 71) and a test group (N = 41) with the observed endpoint of recurrence-free survival (RFS). Features were extracted from the arterial and portal phases of enhanced computed tomography (CT) images and gut microbiome, and features with minimum absolute contraction and selection operator regression were created, and the extracted features were scored to create a preoperative prediction model by using the multivariate Cox regression analysis with risk stratification analysis. Results: In the study cohort, the model constructed by combining radiological and gut flora features provided good predictive performance (C index, 0.811 (0.650-0.972)). The combined radiology and gut flora-based model constructed risk strata with high, intermediate, or low risk of recurrence and different characteristics of recurrent tumor imaging and gut flora. Recurrence of early stage hepatocellular carcinoma may be associated with oxidative stress in the intestinal flora. Conclusions: This study successfully constructs a risk model integrating enhanced CT and gut microbiome characteristics that can be used for the risk of postoperative recurrence in patients with early HCC. In addition, intestinal flora associated with HCC recurrence may be involved in oxidative stress.

Acyl-CoA Binding Domain Containing 4 Polymorphism rs4986172 and Expression Can Serve as Overall Survival Biomarkers for Hepatitis B Virus-Related Hepatocellular Carcinoma Patients After Hepatectomy.

Background: The aim of our study was to evaluate the potential of expression and single nucleotide polymorphism of Acyl-CoA binding domain containing 4 (ACBD4) gene as prognosis biomarkers in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after hepatectomy. Methods: HBV-related HCC patients from the First Affiliated Hospital of Guangxi Medical University and GSE14520 were included in the current study, as well as The Cancer Genome Atlas (TCGA) HCC verification cohort. Prognostic analysis and multiple functional enrichment analysis methods were used to evaluate the prognostic value and potential biological functions of the ACBD4 gene in HBV-related HCC. Results: We found that ACBD4 gene is highly expressed in normal liver tissues and markedly down-regulated in HBV-related HCC tissues. ACBD4 gene was significantly related to overall survival (OS) of HCC in TCGA and GSE14520 cohorts, and patients with low ACBD4 expression were markedly related to poor OS. Rs4986172 was observed as an OS biomarker after hepatectomy in the Guangxi HBV-related HCC cohort. The OS of rs4986172 GG genotype was worse than that of HCC patients with A allele (AA and AG genotypes). Multifunctional enrichment analysis suggested that ACBD4 gene is closely related to the metabolic, peroxisome proliferator-activated receptor and cytochrome P450 pathway. Through connectivity map, we also identified eight compounds that may be used as targeted therapeutic agents for ACBD4 gene in HBV-related HCC; these compounds were scopoletin, alfaxalone, bephenium hydroxynaphthoate, apramycin, 4,5-dianilinophthalimide, DL-thiorphan, aminohippuric acid and quinidine. Immune microenvironment analysis revealed that there were significant differences in immune scores of HBV-related HCC tumor tissues with different ACBD4 expression levels. Conclusion: Our study reveals that ACBD4 expression and rs4986172 can be serve as biomarkers of OS in HBV-related HCC patients after hepatectomy.

Intraoperative Indocyanine Green Retention Test of Left Hemiliver in Decision-Making for Patients With Hepatocellular Carcinoma Undergoing Right Hepatectomy.

Introduction: The aim of this study was to select qualified patients with hepatocellular carcinoma (HCC) who underwent right hepatectomy (RH) via intraoperative indocyanine green retention test at 15 min (ICG-R15) of the left hemiliver, which prevents severe posthepatectomy liver failure (PHLF). Methods: Twenty HCC patients who were preoperatively planned to undergo RH were enrolled. Intraoperative ICG-R15 of left hemiliver was measured after the right Glissonean pedicle was completely blocked. Patients then underwent RH if intraoperative ICG-R15 was ≤ 10%. Otherwise, patients underwent staged RH (SRH), either associating liver partitioning and portal vein ligation for staged hepatectomy (ALPPS) or portal vein ligation (PVL), followed by stage-2 RH. The comparison group consisted of patients with a ratio of standard left liver volume (SLLV) of > 40% and preoperative ICG-R15 ≤ 10% who underwent RH. The clinical outcomes of these two groups were compared. Results: Of the 20 patients, six underwent stage-1 RH, six underwent ALPPS, five underwent PVL followed by stage-2 RH, and three failed to proceed to stage-2 RH after PVL. No significant differences were found among the 17 patients who underwent stage-1 or stage-2 RH in the study group, the 19 patients in the comparison group, the 11 patients in the stage-2 RH group, and the six patients in the stage-1 RH group in incidences of PHLF, postoperative complications, hospital stay, and HCC recurrence within 1 year after RH. Compared with the stage-1 ALPPS group, the mean operative time and blood loss of the stage-1 PVL group were significantly less (p <0.001 and p = 0.022, respectively). The stage-1 PVL group had a significantly longer waiting-time (43.4 vs. 14.0 days, p = 0.016) than the stage-1 ALPPS group to proceed to stage-2 RH. After stage-2 RH, tumor recurrence within 1 year was 20% (1/5) in patients after PVL and 50% (3/6) after stage-1 ALPPS. Conclusions: Intraoperative ICG-R15 ≤ 10% of left hemiliver was valuable in intraoperative decision-making for patients who were planned to undergo RH. There is a possibility that stage-1 PVL might help to select patients with more favorable biological behavior to undergo stage-2 RH.

Diagnosis and prognostic value of C-X-C motif chemokine ligand 1 in colon adenocarcinoma based on The Cancer Genome Atlas and Guangxi cohort.

Objective: The objective was to identify and validate C-X-C motif chemokine ligand 1(CXCL1) for diagnosis and prognosis in colon adenocarcinoma (COAD). Methods: Our current study had enrolled one The Cancer Genome Atlas (TCGA) cohort and two Guangxi cohorts to identify and verify the diagnostic and prognostic values of CXCL1 in COAD. Functional enrichment was performed by gene set enrichment analysis (GSEA). Results: In TCGA cohort, the expression of CXCL1 was significantly up-regulated in tumor tissues and decreased as the tumor stage developed. The receiver operating characteristic (ROC) curve showed that CXCL1 had a high diagnostic value for COAD. The result of Kaplan-Meier survival analysis showed that CXCL1 gene expression (P=0.045) was significantly correlated with overall survival (OS) of COAD. Results of Guangxi cohort also verified the diagnostic value of CXCL1 in COAD, and sub-group survival analyses also suggested that patients with high CXCL1 expression were related to a favorable OS (Corrected P=0.005). GSEA revealed that CXCL1 high expression phenotype was related to cytokine activity, cell apoptosis, P53 regulation pathway, and regulation of autophagy in COAD. Conclusions: In this study, we found that CXCL1 gene might be a potential diagnostic biomarker for COAD, and might serve as a prognostic biomarker for specific subgroup of COAD.

SOX4 as biomarker in hepatitis B virus-associated hepatocellular carcinoma.

Background: Hepatitis B virus infection is associated with liver disease, including cancers. In this study, we assessed the power of sex-determining region Y (SRY)-related high-mobility group (HMG)-box 4(SOX4) gene to predict the clinical course of hepatocellular carcinoma (HCC). Methods: To evaluate the differential expression of SOX4 and its diagnostic and prognostic potential in HCC, we analyzed the GSE14520 dataset. Stratified analysis and joint-effect analysis were done using SOX4 and clinical factor. We then designed a nomogram for predicting the clinical course of HCC. Differential SOX4 expression and its correlation with tumor stage as well as its diagnostic and prognostic value were analyzed on the oncomine and GEPIA websites. Gene set enrichment analysis was explored as well as candidate gene ontology and metabolic pathways modulated by in SOX4 HCC. Results: Our analysis revealed that the level of SOX4 was significantly upregulated in tumor issue (P <0.001). This observation was validated through oncomine dataset and MERAV analysis (all P <0.05). Diagnostic receiver operating characteristic (ROC) analysis of SOX4 suggested it has diagnostic potential in HCC (GSE14520 dataset: P <0.001, area under curve (AUC) = 0.782; Oncomine: (Wurmbach dataset) P = 0.002, AUC = 0.831 and (Mas dataset) P <0.001, AUC = 0.947). In addition, SOX4 exhibited high correlation with overall survival of HBV-associated HCC (adjusted P = 0.004, hazard ratio (HR) (95% confidence interval (CI)) = 2.055 (1.261-3.349) and recurrence-free survival (adjusted P = 0.008, HR (95% CI) = 1.721 (1.151-2.574). These observations which were verified by GEPIA analysis for overall survival (P = 0.007) and recurrence-free survival (P= 0.096). Gene enrichment analysis revealed that affected processes included lymphocyte differentiation, pancreatic endocrine pathways, and insulin signaling pathway. SOX4 prognostic value was evaluated using nomogram analysis for HCC 1, 3, and 5-year, survival. Conclusion: Differential SOX4 expression presents an avenue of diagnosing and predicting clinical course of HCC. In HCC, SOX4 may affect TP53 metabolic processes, lymphocyte differentiation and the insulin signaling pathway.

UXT antisense RNA 1 sever as a novel prognostic long non-coding RNA in early stage pancreatic ductal adenocarcinoma patients after receiving pancreaticoduodenectomy.

Objective: The principal objective of this project was to investigate the prognostic value of UXT antisense RNA 1 (UXT-AS1) in pancreatic ductal adenocarcinoma (PDAC), as well as its biological function mechanisms and the screening of targeted drugs using The Cancer Genome Atlas (TCGA) PDAC genome-wide RNA sequencing (RNA-seq) dataset. Methods: We used TCGA 112 early stage PDAC patients to screen the prognostic value of UXT-AS1. Biological functions and mechanisms of UXT-AS1 were investigated by co-expression analysis, differentially expressed genes (DEGs) and gene set enrichment analysis, while targeted drug screening was investigated by connectivity Map (CMap). Results: By analyzing the dataset from TCGA cohort, we found that UXT-AS1 was significantly up-regulated in pancreatic cancer tissues. Multivariate survival analysis demonstrated that PDAC patients with high UXT-AS1 expression had an unfavourable prognosis (adjusted P=0.033, HR=1.830, 95%CI=1.051-3.188). Genome-wide co-expression analysis and gene set enrichment analysis suggested that UXT-AS1 may act as a pivotal part in PDAC by participating in nuclear factor kappa beta, regulation of tumor necrosis factor, cell adhesion, T cell receptor signaling pathway, and numerous immune-related biological processes and signaling pathways. Functional enrichment analysis of DEGs between high- and low-UXT-AS1 expression groups suggested that these DEGs were significant enriched in B cell receptor complex, response to drug chemical carcinogenesis and drug metabolism-cytochrome P450. CMap analysis revealed that quipazine and terazosin may be targeted drugs for UXT-AS1 in PDAC. Conclusion: Our current study has identified UXT-AS1 as a novel biomarker for the prognosis of early stage PDAC. We also clarified its biological functional mechanisms and identified two targeted drugs of UXT-AS1 in PDAC.

Laparoscopic versus open hepatectomy for hepatocellular carcinoma with cirrhosis: a single-center propensity score matching analysis.

BACKGROUND: Laparoscopic hepatectomy (LH) for hepatocellular carcinoma (HCC) remains controversial due to limited research. This study analyzed the oncology prognosis of patients who received LH treatment for HCC compared with conventional open hepatectomy (OH). METHODS: We conducted a retrospective analysis of patients with cirrhosis who underwent hepatectomy for HCC between 2012 and 2018. Patients were divided into LH and OH groups, and the oncology outcomes were compared before and after 1:1 propensity score matching (PSM). RESULTS: A total of 403 patients with HCC cirrhosis who received LH (n=112) and OH (n=291) were enrolled. After PSM, 106 pairs of patients were matched. Compared with OH before and after PSM, there was no significant difference in overall survival (OS) and relapse-free survival (RFS) between the two groups. Tumor stage, Child-Pugh classification, venous tumor thrombus, tumor size ≥5 cm, and microvascular invasion (MVI) were independent risk factors for postoperative OS in HCC patients with cirrhosis. Tumor size ≥5 cm and MVI were independent risk factors for RFS. CONCLUSIONS: Patients with HCC who underwent LH had a similar OS and RFS compared with those who received traditional open surgery. Therefore, LH can be used as a safe and feasible treatment for patients with HCC.

Genome-wide RNA-sequencing dataset reveals the prognostic value and potential molecular mechanisms of lncRNA in non-homologous end joining pathway 1 in early stage Pancreatic Ductal Adenocarcinoma.

Objective: Our current study is to explore the prognostic value and molecular mechanisms underlying the role of lncRNA in non-homologous end joining pathway 1 (LINP1) in early stage pancreatic ductal adenocarcinoma (PDAC). Methods: Genome-wide RNA-seq datasets of 112 early stage PDAC patients were got from The Cancer Genome Atlas and analyzed using multiple online tools. Results: Overall survival in high LINP1 expression patients was shorter than those with low expression (high-LINP1 vs. low-LINP1=481 vs. 592 days, log-rank P=0.0432). The multivariate Cox proportional hazard regression model suggested that high-LINP1 patients had a markedly higher risk of death than low-LINP1 patients (adjusted P=0.004, hazard ratio=2.214, 95% confidence interval=1.283-3.820). Analysis of genome-wide co-expressed genes, screening of differentially expressed genes, and gene set enrichment analysis indicated that LINP1 may be involved in the regulation of cell proliferation-, cell adhesion- and cell cycle-related biological processes in PDAC. Six small-molecule compounds including STOCK1N-35874, fenofibrate, exisulind, NU-1025, vinburnine, and doxylamine were identified as potential LINP1-targeted drugs for the treatment of PDAC. Conclusions: Our study indicated that LINP1 may serve as a prognostic biomarker of early stage PDAC. Analysis of genome-wide datasets led to the elucidation of the underlying mechanisms and identified six potential targeted drugs for the treatment of early PDAC.

Comprehensive investigation of p53, p21, nm23, and VEGF expression in hepatitis B virus-related hepatocellular carcinoma overall survival after hepatectomy.

Objective: The goal of our current study is to assess the immunohistochemical of p53, p21, nm23, and VEGF expression in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) prognosis after hepatectomy, as well as the prospective molecular mechanisms of prognostic indicator. Methods: There were 419 HBV-related HCC patients who were from southern China of Guangxi province and were used to evaluate the immunohistochemical expression for these biomarkers in prognosis. A genome-wide expression microarray dataset of HBV-related HCC were obtained from GSE14520. Results: In our study, the expression of p53, p21, and nm23 in cancer tissues of patients with hepatitis B-related hepatocellular carcinoma did not affected the clinical outcome of 2 years, 5 years or overall. Patients with high expression of VEGF had a worse overall survival after 2 years of surgery than patients with low expression (adjusted P=0.040, adjusted HR = 1.652, 95% CI = 1.024-2.665). Survival analysis of VEGF in GSE14520 cohort also demonstrated that VEGF mRNA expression also significantly associated with HBV-related HCC OS (adjusted P=0.035, adjusted HR =1.651, 95% CI =1.035-2.634). The prospective molecular mechanisms by co-expression analysis suggested that VEGF might be correlated to regulation of cell proliferation, cell growth and apoptotic process, Rap1 signaling pathway, HIF-1 signaling pathway, PPAR signaling pathway, cell cycle. Whereas the GSEA suggested that VEGF might involve in the regulation of HIF and HIF1A pathway, and TP53 regulation pathway. Conclusion: Our findings suggested that VEGF might be a prognostic indicator of HBV-related HCC, and we also identified the VEGF prospective molecular mechanisms through the whole genome co-expression and GSEA approaches.

Noteworthy prognostic value of phospholipase C delta genes in early stage pancreatic ductal adenocarcinoma patients after pancreaticoduodenectomy and potential molecular mechanisms.

The purpose of this investigation was to explore the prognostic value of phospholipase C delta (PLCD) genes in early stage pancreatic ductal adenocarcinoma (PDAC) and its potential molecular mechanisms. The prognostic value of PLCD genes in early stage PDAC was assessed using the Kaplan-Meier method and multivariate Cox proportional hazards regression model. Genome-wide correlation analysis was performed on PLCD3 to identify the highly correlated genes in the transcriptome. Then, PLCD3 and these correlated genes together underwent a bioinformatics analysis to elucidate the potential molecular biological functions of PLCD3 in PDAC. PLCD1 and PLCD3 are significantly overexpressed in PDAC. In PDAC patients, PLCD3 is overexpressed in certain groups of people with a history of alcoholism (P = .032). High expression of PLCD3 was found to be associated with lower overall survival (OS) of patients with early stage PDAC (P = .020; adjusted P = .016). A combination of PLCD3 and clinical variables was able to better predict the outcome of patients with early stage PDAC. These clinical variables are histological grade (P = .001; adjusted P = .001), targeted molecular therapy (P < .001; adjusted P < .001), radiation therapy (P = .002; adjusted P = .039), and residual resection (P = .001; adjusted P = .002). The bioinformatics analysis revealed that PLCD3 is associated with angiogenesis, intracellular signal transduction, and regulation of cell proliferation. In conclusion, PLCD3 may be a potential prognostic biomarker for early stage PDAC.

Comprehensive investigation of key biomarkers and pathways in hepatitis B virus-related hepatocellular carcinoma.

Objective: Our study is aim to explore potential key biomarkers and pathways in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) using genome-wide expression profile dataset and methods. Methods: Dataset from the GSE14520 is used as the training cohort and The Cancer Genome Atlas dataset as the validation cohort. Differentially expressed genes (DEGs) screening were performed by the limma package. Gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), gene ontology, the Kyoto Encyclopedia of Genes and Genomes, and risk score model were used for pathway and genes identification. Results: GSEA revealed that several pathways and biological processes are associated with hepatocarcinogenesis, such as the cell cycle, DNA repair, and p53 pathway. A total of 160 DEGs were identified. The enriched functions and pathways of the DEGs included toxic substance decomposition and metabolism processes, and the P450 and p53 pathways. Eleven of the DEGs were identified as hub DEGs in the WGCNA. In survival analysis of hub DEGs, high expression of PRC1 and TOP2A were significantly associated with poor clinical outcome of HBV-related HCC, and shown a good performance in HBV-related HCC diagnosis. The prognostic signature consisting of PRC1 and TOP2A also doing well in the prediction of HBV-related HCC prognosis. The diagnostic and prognostic values of PRC1 and TOP2A was confirmed in TCGA HCC patients. Conclusions: Key biomarkers and pathways identified in the present study may enhance the comprehend of the molecular mechanisms underlying hepatocarcinogenesis. Additionally, mRNA expression of PRC1 and TOP2A may serve as potential diagnostic and prognostic biomarkers for HBV-related HCC.

Diagnostic and prognostic biomarkers of Human Leukocyte Antigen complex for hepatitis B virus-related hepatocellular carcinoma.

Background: Hepatitis B virus infection had been identified its relationship with liver diseases, including liver tumors. We aimed to explore diagnostic and prognostic values between the Human Leukocyte Antigen (HLA) complex and hepatocellular carcinoma (HCC). Methods: We used the GSE14520 dataset to explore diagnostic and prognostic significance between HLA complex and HCC. A nomogram was constructed to predict survival probability of HCC prognosis. Gene set enrichment analysis was explored using gene ontologies and metabolic pathways. Validation of prognostic values of the HLA complex was performed in the Kaplan-Meier Plotter website. Results: We found that HLA-C showed the diagnostic value (P <0.0001, area under curve: 0.784, sensitivity: 93.14%, specificity: 62.26%). In addition, HLA-DQA1 and HLA-F showed prognostic values for overall survival, and HLA-A, HLA-C, HLA-DPA1 and HLA-DQA1 showed prognostic values for recurrence-free survival (all P ≤ 0.05, elevated 0.927, 0.992, 1.023, 0.918, 0.937 multiples compared to non-tumor tissues, respectively). Gene set enrichment analysis found that they were involved in antigen processing and toll like receptor signalling pathway, etc. The nomogram was evaluated for survival probability of HCC prognosis. Validation analysis indicated that HLA-C, HLA-DPA1, HLA-E, HLA-F and HLA-G were associated with HCC prognosis of overall survival (all P ≤ 0.05, elevated 0.988 and 0.997 multiples compared to non-tumor tissues, respectively). Conclusion: HLA-C might be a diagnostic and prognostic biomarker for HCC. HLA-DPA1 and HLA-F might be prognostic biomarkers for HCC.

Prognostic value of Kinesin-4 family genes mRNA expression in early-stage pancreatic ductal adenocarcinoma patients after pancreaticoduodenectomy.

BACKGROUND: The aim of this study was to investigate the potential prognostic value of Kinesin-4 family genes mRNA expression in early-stage pancreatic ductal adenocarcinoma (PDAC) patients after pancreaticoduodenectomy. METHODS: Kaplan-Meier survival analysis method with log-rank test and Cox proportional hazards regression analysis were performed to figure out the association between Kinesin-4 family genes expression and PDAC patients overall survival time. Joint-effect survival analysis and stratified survival analysis were carried out to assess the prognosis prediction value of prognosis-related gene. Nomogram was constructed for the individualized prognosis prediction. In addition, we had used the gene set enrichment analysis and genome-wide co-expression analysis to further explore the potential mechanism. RESULTS: KIF21A expression level was significantly associated with PDAC patient clinical prognosis outcome and patient with a high expression of KIF21A would have a shorter overall survival time. The prognosis prediction significance of KIF21A was well validated by the joint-effect survival analysis, stratified survival analysis, and nomogram. Meanwhile, the gene set enrichment analysis and genome-wide co-expression analysis revealed that KIF21A might involve in DNA damage and repair, transcription and translation process, post-translation protein modification, cell cycle, carcinogensis genes and pathways. CONCLUSIONS: Our current research demonstrated that KIF21A could serve as a potential prognostic biomarker for patient with early-stage PDAC after pancreaticoduodenectomy.

Clinical significance and prospective molecular mechanism of C­C motif chemokine receptors in patients with early­stage pancreatic ductal adenocarcinoma after pancreaticoduodenectomy.

The present study aimed to determine the clinical significance and potential molecular mechanisms of C­C motif chemokine receptor (CCR) genes in patients with early­stage pancreatic ductal adenocarcinoma (PDAC). The transcriptomic, survival and clinical data of 112 patients with early­stage PDAC who underwent pancreaticoduodenectomy were obtained from The Cancer Genome Atlas. The prognostic values of the CCR genes involved in early­stage PDAC were evaluated using Kaplan­Meier analysis and the multivariate Cox proportional risk regression model, and the potential molecular mechanisms were determined using bioinformatics tools. The identified CCRs closely interacted with each other at both the gene and protein levels. High expression levels of CCR5 [adjusted P=0.012; adjusted hazard ration (HR)=0.478, 95% confidence interval (CI)=0.269­0.852], CCR6 (adjusted P=0.026; adjusted HR=0.527, 95% CI=0.299­0.927) and CCR9 (adjusted P=0.001; adjusted HR=0.374, 95% CI=0.209­0.670) were significantly associated with longer overall survival times in patients with early­stage PDAC. The contribution of CCR5, CCR6 and CCR9 to the outcome of early­stage PDAC was also demonstrated. Combined survival analysis of CCR5, CCR6 and CCR9 suggested that patients with high expression levels of these CCRs exhibited the most favorable outcomes. A prognostic signature was constructed in terms of the expression level of CC5, CCR6 and CCR9, and time­dependent receiver operating characteristic curves indicated that this signature was able to effectively predict the outcome of patients with early­stage PDAC. The potential molecular mechanisms of CCR5, CC6 and CCR9 in PDAC include its intersection of the P53, nuclear factor (NF)­κB, generic transcription, mitogen­activated protein kinase and STAT signaling pathways. Collectively, this highlights that CCR5, CCR6 and CCR9 are potential prognostic biomarkers for early­stage PDAC.

Diagnostic and prognostic value of WNT family gene expression in hepatitis B virus­related hepatocellular carcinoma.

The aim of the present study was to investigate the diagnostic and prognostic value of Wingless­type MMTV integration site (WNT) gene family expression in patients with hepatitis B virus (HBV)­related hepatocellular carcinoma (HCC). The clinical data of the patients and gene expression levels were downloaded from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Receiver operating characteristic curve analysis was used to investigate the diagnostic value of WNT genes. Cox proportional hazard regression analysis and Kaplan­Meier survival analysis were performed to evaluate the association of WNT gene expression level with overall survival (OS) and recurrence­free survival (RFS). A nomogram was constructed for the prediction of prognosis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Diagnostic receiver operating characteristic curve analysis suggested that WNT2 had a high diagnostic value, with an area under the curve (AUC) of >0.800 (P<0.0001, AUC=0.810, 95% CI: 0.767­0.852). Survival analysis indicated that the expression level of WNT1 was significantly associated with OS and RFS (adjusted P=0.033, adjusted HR=0.607, 95% CI: 0.384­0.960; and adjusted P=0.007, adjusted HR=0.592, 95% CI: 0.404­0.868, respectively). In the TCGA validation cohort, we also observed that WNT2 was significantly differentially expressed between HCC tissues and adjacent non­tumor tissues, and WNT1 was associated with both the OS and RFS of HCC. Therefore, through the GSE14520 HBV­related HCC cohort we concluded that WNT2 may serve as a diagnostic biomarker and WNT1 may serve as a prognostic biomarker. These results may also be extended to TCGA HCC verification cohort.

Clustered microRNAs hsa-miR-221-3p/hsa-miR-222-3p and their targeted genes might be prognostic predictors for hepatocellular carcinoma.

Objective: MicroRNAs (miRNAs) have been explored in malignancies. We investigated the functions of clustered miRNAs hsa-miR-221/222-3p in hepatocellular carcinoma (HCC). Methods: Human miRNA tissue atlas website was determined expression levels in liver tissue. Four databases, TarBase, miRTarBase, miRecords and miRPathDB, were found experimentally validated target genes of clustered miRNAs. TargetScanHuman was predicted target genes. The STRING website was depicted protein-protein interaction (PPI) networks. The OncoLnc website analyzed prognostic values for hsa-miR-221/222-3p and their target genes. The MCODE plugin calculated modules of PPI networks. Receiver operating characteristic (ROC) curves were predicted 1, 3, and 5 years prognostic values. Results: Expression of clustered miRNAs was high in liver tissues. A total of 1577 target genes were identified. Enrichment analysis showed that target genes were enriched mainly in cancer, Wnt signaling and ErbB signaling pathways. Two modules were calculated using PPI networks. Has-miR-221-3p was not associated with prognosis (P = 0.401). Has-miR-222-3p and target genes ESR1, TMED7, CBFB, ETS2, UBE2J1 and UBE2N of the clustered miRNAs were associated with HCC survival (all P < 0.05). Has-miR-222-3p, CBFB, and UBE2N showed good performance of ROC in prognosis prediction at 1, 3, and 5 years (all area under curves > 0.600). Conclusion: Has-miR-222-3p and target genes, especially CBFB, UBE2N, may serve as prognostic predictors for HCC.