Prognostic Marker For Hepatocellular Carcinoma Research Articles

Prognostic values of immune scores and immune microenvironment-related genes for hepatocellular carcinoma.

It is crucial to grasp the characteristics of tumour immune microenvironment to improve effects of immunotherapy. In this study, the immune and stromal scores of 371 cases were calculated for quantitative analysis of immune and stromal cell infiltration in the tumour microenvironment of hepatocellular carcinoma (HCC). The weighted gene co-expression network analysis and protein–protein interaction network were analysed to identify immune microenvironment-related genes. The results showed that patients with high immune scores had a higher 4-year recurrence-free rate. TP53, CTNNB1, and AXIN1 mutations significantly varied with immune scores. In immune score-related modules analysis, Kyoto encyclopaedia of genes and genomes pathways and gene ontology terms were closely related to immune processes, tumorigenesis, and metastasis. Twelve new immune microenvironment-related genes were identified and had significantly positive correlations with seven immune checkpoint genes. In prognostic analysis, eleven immune microenvironment-related genes exhibited high expression, nine of which were validated in the GSE62232 dataset and were significantly associated with a good prognosis. Our findings suggest that calculating immune score and stromal score could help to determine tumour purity and immune cell infiltration in the tumour microenvironment. Nine immune microenvironment-related genes identified in this study had potential as prognostic markers for HCC.

HMex-3A is associated with poor prognosis and contributes to the progression of hepatocellular carcinoma

BackgroundHMex-3A, an RNA-binding protein, was found to be associated with tumorigenesis. However, the roles of hMex-3A in hepatocellular carcinoma (HCC) progression remained unclear. MethodsThe different expression of hMex-3A between HCC tissues and non-tumor tissues was evaluated using The Cancer Genome Atlas database. Thereafter, the hMex-3A expression was evaluated in HCC tissues using Western blotting and qRT-PCR. Immunohistochemistry was performed to investigate the association between hMex-3A level and clinicopathological features including prognosis in HCC patients. In addition, we used si-hMex-3A to knockdown hMex-3A in HCC cells to test Cell Counting Kit-8, colony formation, cell migration and invasion. ResultsThe hMex-3A expression was significantly elevated in HCC tissues. Analysis of the clinicopathological parameters suggested that hMex-3A expression was significantly associated with pathological grade (P = 0.019) and TNM stage (P = 0.001) in HCC. Moreover, univariate and multivariate Cox-regression analyses revealed that high hMex-3A expression (HR = 1.491, 95% CI: 1.107–2.007; P = 0.009) was an independent risk factor for overall survival in HCC patients. Finally, we confirmed that si-hMex-3A could significantly inhibit HCC cell proliferation, migration, and invasion in vitro. ConclusionsHMex-3A may contribute to the progression of HCC and might be used as a novel therapeutic target and prognostic marker in HCC.

Increased KIF21B expression is a potential prognostic biomarker in hepatocellular carcinoma.

BACKGROUNDThe kinesin superfamily protein member KIF21B plays an important role in regulating mitotic progression; however, the function and mechanisms of KIF21B in cancer, particularly in hepatocellular carcinoma (HCC), are unknown.AIMTo explore the role of KIF21B in hepatocellular carcinoma and its effect on prognosis after hepatectomy.METHODSFirst, data on the differential expression of KIF21B in patients with HCC from The Cancer Genome Atlas database was analyzed. Subsequently, the expression levels of KIF21B in HCC cell lines and hepatocytes were detected by reverse transcription-polymerase chain reaction, and its biological effect on BEL-7404 cells was evaluated by KIF21B knockdown. Immunohistochemical analysis was used to validate the differential expression of KIF21B in HCC tissues and adjacent normal tissues from 186 patients with HCC after hepatectomy. The Kaplan-Meier method was used to assess prognosis significance.RESULTSKIF21B expression levels were significantly higher in HCC tissues than in corresponding adjacent normal tissues. The expression levels of KIF21B in four HCC cell lines were higher than that in normal liver cells. Functional experiments showed that KIF21B knockdown remarkably suppressed cell proliferation and induced apoptosis. Moreover, immunohistochemistry results are consistent with The Cancer Genome Atlas analysis, with KIF21B expression levels being increased in HCC tissues compared to adjacent normal tissues. Univariate and multivariate analyses revealed KIF21B as an independent risk factor for overall survival and disease-free survival in patients with HCC after hepatectomy.CONCLUSIONTaken together, our results provide evidence that KIF21B plays an important role in HCC progression and may be a potential diagnostic and prognostic marker for HCC.

Synthesis and biological evaluation of gold(III) Schiff base complexes for the treatment of hepatocellular carcinoma through attenuating TrxR activity

Hepatocellular carcinoma (HCC) is one of the most common cancers and a leading cause of death worldwide. Increased thioredoxin reductase (TrxR) levels were recently identified as possible prognostic markers for HCC. Here, four gold(III) complexes 1b-4b bearing Schiff base ligands were synthesized, characterized, and screened for antitumor activity against HCC. All complexes triggered significant antiproliferative effects against HCC cells, especially the most active complex 1b induced HepG2 cells apoptosis by activating the endoplasmic reticulum stress (ERS). 1b could clearly inhibit the TrxR activity to elevate reactive oxygen species (ROS), mediate ERS and lead to mitochondrial dysfunction. Notably, treatment of 1b improved the CCl4-induced liver damage in vivo by down-regulation of TrxR expression and inflammation level.

Epithelial V-like antigen 1 promotes hepatocellular carcinoma growth and metastasis via the ERBB-PI3K-AKT pathway.

The role of epithelial V‐like antigen 1 (EVA1) has been well studied in thymic development and homostasis; however, its putative relationship with cancer remains largely unknown. Therefore, here we investigated the role of EVA1 in hepatocellular carcinoma. Interestingly, EVA1 expression was significantly increased in hepatocellular carcinoma (HCC) and was also associated with a poor prognosis and recurrence in HCC patients. Overexpression of EVA1 promoted cell growth, invasion and migration in vitro. Consistently, knockdown of EVA1 expression inhibited proliferation and migration in vitro, while repressing metastasis of HCC cells in vivo. RNA‐seq analysis indicated that EVA1 is able to upregulate the expression of genes in the ERBB3‐PI3K pathway. Accordingly, an increased level of AKT phosphorylation was detected in HCC cells after EVA1 overexpression. LY294002, a PI3K inhibitor, inhibited AKT phosphorylation and rescued the tumor‐promoting effect of EVA1 overexpression. Altogether, the present study has revealed the oncogenic role of EVA1 during HCC progression and metastasis through the ERBB‐PI3K‐AKT signaling pathway, reiterating the potential use of EVA1 as a therapeutic target and/or prognostic marker for HCC.

Evaluation of Ferritin and Transferrin Ratio as a Prognostic Marker for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) has tripled in incidence over the past 20years and now ranks as the third leading cause of mortality attributed to cancer. Underlying pathophysiology is sustained hepatic inflammation which results in hepatocellular dysplasia and thus an environment prone to HCC. Considering the essential role of inflammation in the pathogenesis of HCC, we evaluated the prognostic utility of ferritin-transferrin ratio (FTR) in HCC. We retrospectively reviewed the electronic medical records of patients with HCC (diagnosed on radiographic criteria and/or biopsy) from 2000 through 2015. We collected data regarding the patient demographics, laboratory investigations at the time of HCC diagnosis and prior to the initiation of treatment. Overall survival was calculated from the time of diagnosis, cases were censored at the date of last follow-up, if date of death was not known. Kaplan-Meier curves were estimated to evaluate the prognostic significance of FTR. Receiver operating characteristics (ROC) curve was plotted for FTR to predict mortality and identify cut-off value by optimized Youden's index. Among the 176 patients identified by initial screening, 116 patients were eventually included for analysis. Overall median survival was 11.9months. FTR, of note, was significantly lower in alive (6.9, p < 0.001). In univariate analysis, alfa-fetoprotein (AFP), aspartate aminotransferase (AST), serum ferritin (SF), transferrin (TFS), and FTR were significantly associated with mortality. On multivariate analysis for mortality, FTR, AFP, and epidemiologic factors predictive of mortality including male gender and advanced HCC were significant. The ferritin-transferrin ratio (FTR), calculated at the time of HCC diagnosis could predict mortality in our cohort of patients. With an optimal cut-off of 7.7 for FTR were stratified into high- and low-risk groups. The hazard ratio between the two groups was 2.36 (p < 0.003). Future studies with longitudinal follow-up of FTR at intervals and important time points (e.g., perioperative) might provide more insights to its prognostic value.

The expression status of ZIC2 is an independent prognostic marker of hepatocellular carcinoma

BackgroundZinc finger protein of cerebellum 2 (ZIC2) is a transcriptional activator or repressor that is important for the organogenesis of the central nervous system. Previous studies have reported that ZIC2 is widely upregulated in a variety of tumors. MethodsOncomine database was used to evaluate the expression levels of ZIC2 in hepatocellular carcinoma (HCC) and normal liver tissues. Quantitative real-time polymerase chain reaction and immunohistochemistry were conducted to validate the results from the database. Cox regression analysis and survival curves were performed to assess the survival effect of ZIC2 in HCC. ResultsIncreased expression of ZIC2 was detected in HCC tissues compared with normal liver tissues. In addition, patients with high ZIC2 levels had a poor prognosis. Multivariate analysis showed that clinical stage (T or M classification) and ZIC2 levels were independent prognostic factors for overall survival. Moreover, a subgroup analysis revealed that patients with moderate or poor grade tumors, T1–2 tumors, N0 tumors, early American Joint Committee on Cancer (AJCC) stage, and old age were more likely to present with overexpression of ZIC2. To conclude, ZIC2 is upregulated in HCC and associated with the histology and survival of HCC patients. ConclusionsThe expression status of ZIC2 may serve as an independent prognostic marker of HCC.

Malondialdehyde and C-reactive protein as prognostic markers of hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the most common type of liver cancer. Many factors are related to progression of cirrhosis to HCC and poor outcomes in patients with chronic hepatitis C virus(HCV) ...

CCNB2, NUSAP1 and TK1 are associated with the prognosis and progression of hepatocellular carcinoma, as revealed by co-expression analysis.

The mortality rate associated with hepatocellular carcinoma (HCC) is the third highest among all digestive system tumors. However, the causes of HCC development and the underlying mechanisms have remained to be fully elucidated. In the present bioinformatics study, genetic markers were identified and their association with HCC was determined. The mRNA expression datasets GSE87630, GSE74656 and GSE76427 were downloaded from the Gene Expression Omnibus (GEO) database. A total of 96 differentially expressed genes (DEGs) were screened from the 3 GEO datasets, including 25 upregulated and 71 downregulated genes. DEGs were uploaded to the database for Annotation, Visualization and Integrated Discovery to screen for enriched Gene Ontology terms in various categories and the Search Tool for the Retrieval of Interacting Genes/Proteins was used to identify the interactions and functions of the DEGs. A total of 3 genetic markers were identified in a stepwise pathway and functional analysis in a previous study. The association of the genetic markers with prognosis was analysed using the UALCAN online analysis tool. Regression analysis was also performed to identify the relationship between HCC grade and disease recurrence and the expression of genetic markers using The Cancer Genome Atlas HCC dataset. In addition, the expression of the 3 genetic markers in HCC tissues was determined using reverse transcription-quantitative PCR, the Oncomine database and the Human Protein Atlas database. The expression levels of the 3 genetic markers cyclin B2 (CCNB2), nucleolar and spindle-associated protein 1 (NUSAP1) and thymidine kinase 1 (TK1) were significantly correlated with each other and high mRNA expression of CCNB2 was significantly associated with poor overall survival of patients with HCC. Receiver operating characteristic curve analysis indicated that NUSAP1 and TK1 were capable of distinguishing between recurrent and non-recurrent HCC. Furthermore, CCNB2, NUSAP1 and TK1 were highly correlated with the HCC grade. It was also indicated that the mRNA expression of CCNB2, NUSAPA and TK1 was increased in primary HCC tissues when compared with that in adjacent tissues. The present study identified that the CCNB2, NUSAP1 and TK1 genes may serve as prognostic markers for HCC, and may be of value from the perspectives of basic research and clinical treatment of HCC.

MiR-939-3p promotes epithelial-mesenchymal transition and may be used as a prognostic marker in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common types of cancer worldwide with a high morbidity and mortality rate. An increasing number of studies have demonstrated that microRNAs (miRNAs) serve an important role in HCC. The present study investigated the role of miR-939-3p in HCC. It was demonstrated that miR-939-3p was upregulated in HCC cell lines and HCC tissues compared with normal liver cell lines and paired normal tissues, respectively. It was also found that upregulation of miR-939-3p expression levels in HCC tissues was associated with a less favorable prognosis. Moreover, the overexpression of miR-939-3p in LM3 cells enhanced the metastatic capacity of these cells and promoted epithelial-mesenchymal transition (EMT). In contrast, miR-939-3p inhibition decreased the invasive capacity of HCC cells and EMT. Potential binding target of miR-939-3p to estrogen receptor 1 (ESR1) were predicted using TargetScan. The expression levels of miR-939-3p were negatively associated with ESR1 in HCC tissues based on data from The Cancer Genome Atlas. A luciferase reporter assay was used to confirm ESR1 as a direct downstream target of miR-393-3p. The miR-939-3p/ESR1 axis may be a potential novel target for the treatment of HCC.

Upregulation of FEN1 Is Associated with the Tumor Progression and Prognosis of Hepatocellular Carcinoma.

Background Studies show that patients with hepatocellular carcinoma (HCC) have poor prognosis, particularly when patients are diagnosed at late stages of the disease development. The flap endonuclease 1 (FEN1) gene is overexpressed in multiple malignant tumors and may promote tumor aggressiveness. However, its expression profile and functional roles in HCC are still unclear. Here, we evaluated the molecular mechanisms of FEN1 in HCC. Methods The expression of FEN1 in HCC was evaluated using HCC mRNA expression data from TCGA and GEO databases. The expression of FEN1 was also confirmed by immunohistochemistry (IHC) using a tissue microarray (TMA) cohort with a total of 396 HCC patients. Kaplan-Meier analysis and univariate and multivariate Cox regression analyses were used to determine the correlation between FEN1 expression and survival rate of HCC patients. The molecular mechanism and biological functions of FEN1 in HCC were predicted using functional and pathway enrichment analysis in vitro experiments. Results FEN1 was overexpressed in multiple HCC cohorts at both mRNA and protein levels. The receiver operating characteristic (ROC) curve showed that FEN1 can serve as a diagnostic predictor of HCC. Meanwhile, patients with high FEN1 expression levels showed lower overall survival (OS) and relapse-free survival (RFS) rates than those with low FEN1 expression. More importantly, we found that FEN1 elevation was an independent prognostic factor for OS and RFS in HCC patients based on univariate and multivariate analyses, indicating that FEN1 might be a potential prognostic marker in HCC. Furthermore, knocking down FEN1 resulted in suppressed cell proliferation and migration in vitro. This could have been due to regulation expressions of c-Myc, survivin, and cyclin D1 genes, indicating that FEN1 may function as an oncogene through its role in the cell cycle and DNA replication pathway. Conclusion Our study indicated that high FEN1 expression might function as a biomarker for diagnosis and prognosis. In addition, the study confirms that FEN1 is an oncogene in HCC progression.

Lipid desaturation-associated endoplasmic reticulum stress regulates MYCN gene expression in hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide due to its high rate of recurrence, in part because of cancer stem cell (CSC)-dependent “field cancerization”. Recently, we identified that the oncogene v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) marked CSC-like subpopulations in heterogeneous HCC and served as a therapeutic target and prognostic marker for HCC. In this study, we explored the molecular basis of upregulated MYCN gene expression in HCC cells. Liquid chromatograph time-of-flight mass spectrometry-based metabolome analysis demonstrated that the content of unsaturated fatty acids was increased in MYCN high expression (MYCNhigh) CSC-like HCC cells. Inhibition of lipid desaturation using either the chemical inhibitor or siRNA/shRNA against stearoyl-CoA desaturase-1 (SCD1) suppressed cell proliferation as well as MYCN gene expression in MYCNhigh HCC cells, grown as both monolayer and spheres. Further mechanistic study using RNA-seq based transcriptome analysis revealed that endoplasmic reticulum (ER) stress related signaling networks such as endocannabinoid cancer inhibition pathway were under the control of SCD1 in MYCNhigh HCC cells. Furthermore, the expression of ER stress-inducible transcription suppressor cyclic AMP-dependent transcription factor (ATF3) was downregulated in MYCNhigh CSC-like HCC cells and CSC-rich spheroids, which was upregulated by inhibition of lipid desaturation or treatment with acyclic retinoid (ACR). Lipid profiling using NMR spectroscopy revealed that the ACR dramatically reduced the content of unsaturated fatty acids in HCC cells. The chemical inducer of ER stress inhibited MYCN gene expression, while the chemical inhibitor of ER stress or knockdown of ATF3 gene expression partially rescued the suppression of MYCN gene expression by ACR in MYCNhigh HCC cells. These data suggested that lipid desaturation-mediated ER stress signaling regulates MYCN gene expression in HCC cells and serves as a promising therapeutic target for the treatment and prevention of HCC.

High Paip1 Expression as a Potential Prognostic Marker in Hepatocellular Carcinoma.

Translation plays an important role in the carcinogenesis of various human tumors. Paip1 and eIF4A1 are translation-associated proteins that mediate the function of eukaryotic initiation factor 4F complex. This study aimed to analyse the relationship between the expression status of Paip1 and eIF4A1 and clinicopathologic features in hepatocellular carcinoma (HCC). Immunohistochemical analysis was used to evaluate the expression status of Paip1 and eIF4A1. Two pathologists independently interpreted the immunostained slides. The prognostic value of Paip1 and eIF4A1 was evaluated by the Kaplan-Meier plotter. Among 173 HCC patients, 28 (16.1%) and 46 (26.6%) belonged in the Paip1 and eIF4A1 high-expression groups. High expression of Paip1 and eIF4A1 was associated with advanced TNM stage and more frequent vascular tumor invasion. Univariate analysis indicated that high Paip1 expression was associated with worse five-year overall survival (OS). Public dataset analysis by Kaplan-Meier plotter revealed that high mRNA expression of Paip1, and not of eIF4A1, was significantly associated with worse five-year OS and disease-free survival. Paip1 expression has a potential prognostic value in human HCC.

Diagnostic and prognostic value of lncRNA cancer susceptibility candidate 9 in hepatocellular carcinoma.

BACKGROUNDHepatocellular carcinoma (HCC) is a common malignant gastrointestinal tumor. There are currently few clinical diagnostic and prognostic markers for HCC. LncRNA cancer susceptibility candidate 9 (CASC9) is a long-chain non-coding RNA discovered in recent years, and previous studies have found that lncRNA CASC9 participates in the occurrence and development of HCC, but its clinical value remains unclear.AIMTo determine the expression of lncRNA CASC9 in HCC and its diagnostic and prognostic value.METHODSData on CASC9 expression in patients with HCC were collected from the Cancer Genome Atlas (TCGA) database to analyze the relationship between CASC9 and patient survival. A total of 80 HCC patients treated in The First Affiliated Hospital of Guangxi Medical University from May 2012 to January 2014 were enrolled in the patient group, and 50 healthy subjects were enrolled in the control group during the same period. CASC9 expression in the two groups was determined using quantitative real-time polymerase chain reaction, and its diagnostic and prognostic value was analyzed based on the CASC9 data and pathological data in these HCC patients. The relationship between CASC9 and patient survival was assessed during the 5-year follow-up period.RESULTSAnalysis of data from TCGA database revealed that control samples showed significantly lower CASC9 expression than carcinoma tissue samples (P < 0.001); the low CASC9 expression group had a higher survival rate than the high CASC9 expression group (P = 0.011), and the patient group showed significantly increased expression of serum CASC9, with the area under the curve (AUC) of 0.933. CASC9 expression was related to tumor size, combined hepatitis, tumor, node, metastasis (TNM) staging, lymph node metastasis, differentiation and alpha fetoprotein, and the high CASC9 expression group showed lower 1-year, 3-year and 5-year survival rates than the low CASC9 expression group (all aP < 0.05). Multivariate Cox regression analysis revealed that TNM staging, lymph node metastasis, differentiation, alpha fetoprotein and CASC9 were independent factors affecting the prognosis of patients. Stage I+II patients with lymph node metastasis, low differentiation, and alpha fetoprotein > 200 ng/mL had a poor 5-year survival rate.CONCLUSIONHigh CASC9 expression is beneficial in the prognosis of HCC patients. CASC9 is expected to be a potential diagnostic and prognostic indicator of HCC.

\u03b1-Fetoprotein (AFP)-L3% and transforming growth factor B1 (TGFB1) in prognosis of hepatocellular carcinoma after radiofrequency

BackgroundNumerous hepatocellular carcinoma (HCC) biomarkers have been assessed in the diagnosis and prognosis of HCC. The aim of this study was to assess the value of α-fetoprotein (AFP)-L3% and transforming growth factor B1 (TGFB1) as prognostic markers in hepatocellular carcinoma after radiofrequency ablation (RFA). This observational cohort study included 40 patients with HCC diagnosed by triphasic computed tomography criteria indicated for radiofrequency ablation. Serum AFP, AFP-L3%, and TGFB1 were measured in all patients before and 3 months after radiofrequency ablation.ResultsStatistically significant lower levels of TGFB1, AFP, and AFP-L3% were noted in the HCC patients after radiofrequency ablation. Significant lower levels of TGFB1, AFP, and AFP-L3% were found in the no recurrence group in comparison to the recurrence group. The cutoff value of TGFB1 > 56.87 ng/mL, AFP > 74.9 ng/mL, and AFP-L3% > 8.5% was the best in the discrimination of tumor recurrence with sensitivity of 85.7%, 57.1%, and 100%; specificity of 54.6%, 84.9%, and 100%; and diagnostic accuracy of 64.5%, 69%, and 100%, respectively.ConclusionTGFB1 and AFP-L3% are good prognostic markers for HCC. They could be used to monitor the response of HCC to treatment.

S100A14 protein as diagnostic and prognostic marker in hepatocellular carcinoma

BackgroundProtein S100A14 has recently been implicated in the progress of several types of cancers. This study aimed to investigate the clinical significance of S100A14 in the diagnosis of hepatocellular carcinoma (HCC).ResultsS100A14 was significantly elevated in the HCC group. A cut-off value for serum S100A14 between the HCC group and cirrhosis group is > 0.47 with a sensitivity of 100% and specificity of 88.57%. S100A14 level was a significant diagnostic factor for HCC and a good reference for HCC progression.ConclusionThese results suggest that S100A14 is a good diagnostic marker for HCC.

Expression and significance of ETFDH in hepatocellular carcinoma

The ETFDH (electron transfer flavoprotein dehydrogenase) gene mutations are reported to be a major cause of riboflavin-responsive multiple acyl-coenzyme A dehydrogenation deficiency (MADD). However, the role of ETFDH in the prognosis of hepatocellular carcinoma (HCC) remains unclear. The aim of this study was to investigate the expression of ETFDH in HCC. Immunohistochemical staining of the 207 HCC tissue microarray showed that expression of ETFDH was significantly decreased in HCC compared with the matching noncancerous hepatic tissues (P < 0.001). Moreover, ETFDH expression levels were found to be correlated with AFP levels (P = 0.011). Intriguingly, ETFDH expression levels were significantly lower in poorly differentiated or undifferentiated HCCs as compared to the well or moderately differentiated cases (P = 0.001). Kaplan-Meier analysis revealed that low tumor expression of ETFDH was associated with a poorer overall survival in patients with HCC (P = 0.024). Furthermore, multivariate analysis showed that ETFDH (P = 0.047) was an independent predictor of overall survival. Our findings may shed new light on the identification of new prognostic marker for HCC.

Homocysteine Serum Levels as Prognostic Marker of Hepatocellular Carcinoma with Portal Vein Thrombosis.

Portal vein thrombosis (PVT) is a common complication of endstage hepatocellular carcinoma (HCC). The aim of our study was to evaluate the role of Homocysteine (Hcy) in HCC patient with PVT. Hcy is a sulphur amino-acid involved in two pathways, trans-sulphuration and remethylation, that involve vitamins B6, B12 and folates. We recruited 54 patients with HCC and PVT, 60 patients with HCC and without PVT and 60 control subjects. We measured serum levels of Hcy, folate, vitamins B6 and B12. The comparison between HCC patients with PVT versus HCC without PVT was shown that mean values of Hcy were 6.4 nmol/L (p<0.0073) higher, LDL cholesterol were 4.8 mg/dl (p<0.0079) lower, vitamin B6 were 4.6 nmol/L(p=0.0544) lower, vitamins B 12 were 22.1 pg/ml (p=0.0001) lower. High serum levels of Hcy are an established thrombotic risk factor in the general population. We found significantly higher levels of Hcy in HCC patients with PVT versus both HCC patients without PVT and controls.

The interaction between microRNA-152 and DNA methyltransferase-1 as an epigenetic prognostic biomarker in HCV-induced liver cirrhosis and HCC patients.

The necessity for early detection and hence improving the outcome of treatment of hepatocellular carcinoma (HCC) is critical especially in Hepatitis C virus (HCV)-Genotype 4 induced cases. In our current work, we examined the miRNA-152 and DNMT-1 expression in chronic liver disease (CLD) due to HCV genotype 4 infection with/without cirrhosis and HCC patients as an attempt to evaluate the potential benefits of these new circulating, noninvasive, prognostic, epigenetic markers for liver cirrhosis and carcinogenesis of Egyptian patients. Eighty subjects were included in this study, divided into two groups; group I (40 patients) were classified into subgroup Ia (CLD without cirrhosis, n = 18) and subgroup Ib (CLD with cirrhosis, n = 22), group II (CLD patients with HCC, n = 20), and control (Healthy volunteer, n = 20). The expression of miRNA-152 and DNMT-1 genes were analyzed using Real-Time PCR. MiRNA-152 showed a persistent and significant downregulation in all diseased groups, which was in consistence with the progression of the disease toward the HCC stage. DNMT-1 showed upregulation in all diseased groups when compared to control and subgroup Ia. The miRNA-152 was shown to correlate inversely with DNMT-1 in subgroup Ia, Ib and group II (r = -0.557, p < 0.01), (r = -0.850, p < 0.001) and (r = -0.544, p < 0.02) respectively. In addition, miRNA-152 and DNMT-1 showed a diagnostic ability to discriminate between cases of cirrhosis and HCC against CLD without cirrhosis (p < 0.01), while DNMT-1 did not, except between HCC and cirrhotic cases. Furthermore, both genes can be considered as predictor and prognostic parameters for cirrhosis (OR = 1.041, p = 0.043) and (OR = 1.039, p = 0.04) respectively, while miRNA-152 alone is proved as a prognostic marker for HCC (OR = 1.003, p = 0.044). Finally, the persistent reverse correlation between miRNA-152 with DNMT-1 prompts their use as noninvasive prognostic biomarkers for HCV induced liver cirrhosis and HCC in HCV Genotype 4 patients.

Prognostic Values of Immune Scores and Immune Microenvironment-Related Genes for Hepatocellular Carcinoma

Background: Immunotherapy, as a very promising treatment, has the potential to change the therapeutic landscape for malignancies. However, due to the complexity of immunotherapy and the heterogeneity of Hepatocellular carcinoma (HCC), it is crucial to grasp the characteristics of the tumour immune microenvironment to improve effects of immunotherapy. Methods: The ESTIMATE (Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data) algorithm was used to calculate the immune and stromal scores for quantitative analysis of immune and stromal cell infiltration in HCC. The weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) network were analysed to identify immune microenvironment-related genes. Findings: Immune and stromal scores calculated by ESTIMATE closely represented immune cell components in the tumour microenvironment. Patients with high immune scores had a higher 4-year survival rate. TP53, CTNNB1, and AXIN1 mutations significantly varied with immune scores. In immune score-related modules analysis, Kyoto encyclopaedia of genes and genomes (KEGG) pathways and gene ontology (GO) terms were closely related to immune processes, tumorigenesis, and metastasis. Twelve new immune microenvironment-related genes were identified and had significantly positive correlations with seven checkpoint genes. In prognostic analysis, eleven immune microenvironment-related genes exhibited high expression, nine of which were validated in the GSE62232 dataset and were significantly associated with a good prognosis (P<0.05). Interpretation: Calculating immune score and stromal score could help to determine tumour purity and immune cell infiltration in the tumour microenvironment. Nine immune microenvironment-related genes identified in this study had potential as prognostic markers for HCC. Funding Statement: This research received no external funding. Declaration of Interests: The authors have declared that no conflict of interest exists Ethics Approval Statement: The data from TCGA, GEO and The Human Protein Atlas were all publicly available and open access, so no approval was needed from the ethics committees.