Clinicopathological Features Of Hepatocellular Carcinoma Research Articles

Prognostic and clinicopathological significance of systemic inflammation response index in patients with hepatocellular carcinoma: a systematic review and meta-analysis.

It is unclear whether the systemic inflammation response index (SIRI) can predict the prognosis of patients with hepatocellular carcinoma (HCC). Consequently, the present study focused on systematically identifying the relationship between SIRI and the prognosis of patients with HCC through a meta-analysis. Systematic and comprehensive studies were retrieved from PubMed, Web of Science, Embase, and the Cochrane Library from their inception to August 10, 2023. The role of SIRI in predicting overall survival (OS) and progression-free survival (PFS) in HCC was determined using pooled hazard ratios (HRs) and 95% confidence intervals (CIs). Odds ratios (ORs) and 95% CIs were pooled to analyze the correlations between SIRI and the clinicopathological features of HCC. Ten articles involving 2,439 patients were included. An elevated SIRI was significantly associated with dismal OS (HR=1.75, 95% CI=1.52-2.01, p<0.001) and inferior PFS (HR=1.66, 95% CI=1.34-2.05, p<0.001) in patients with HCC. Additionally, according to the combined results, the increased SIRI was significantly related to multiple tumor numbers (OR=1.42, 95% CI=1.09-1.85, p=0.009) and maximum tumor diameter >5cm (OR=3.06, 95% CI=1.76-5.30, p<0.001). However, the SIRI did not show any significant relationship with sex, alpha-fetoprotein content, Child-Pugh class, or hepatitis B virus infection. According to our results, elevated SIRI significantly predicted OS and PFS in patients with HCC. Moreover, the SIRI was significantly associated with tumor aggressiveness. https://inplasy.com/inplasy-2023-9-0003/, identifier INPLASY202390003.

Cytoplasmic Expression of the EGFL6 Protein Is an Independent Prognostic Factor for Shortened Patient Survival in Human Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver tumor and the second leading cause of cancer-related deaths worldwide. The current study aimed to investigate the clinical relevance of the epidermal growth factor-like domain multiple 6 (EGFL6) expression in HCC and to evaluate whether the expression of EGFL6 in HCC has diagnostic and prognostic significance. This study aimed to investigate EGFL6 protein expression levels in 260 HCC tissue specimens using immunohistochemical analyses. The immunohistochemical study demonstrated strong EGFL6 expression in the cytoplasm of non-tumor or normal hepatocytes. The findings revealed that 98 patients exhibited low EGFL6 expression, while 162 patients displayed high EGFL6 expression. We explored the associations between cytoplasmic EGFL6 expression and the clinicopathological features of HCC. Decreased cytoplasmic EGFL6 expression exhibited significant correlations with worse cellular differentiation, higher T classification, vascular invasion, higher stage, and tumor recurrence. Survival analyses, using Kaplan-Meier survival curves for HCC patients, revealed that those with reduced cytoplasmic EGFL6 expression experienced significantly worse disease-free survival (DFS) and disease-specific survival (DSS). Univariate and multivariate analyses identified EGFL6 as an independent predictor for decreased expression, differentiation grade, vascular invasion, stage, or recurrence in cases of DFS or DSS in HCC. This study represents, to the best of our knowledge, the first investigation into the expression of EGFL6 protein in HCC. Taken together, our findings strongly suggest that EGFL6 likely plays a crucial role in the pathogenesis of HCC and indicates that targeting EGFL6 could be a promising therapeutic strategy.

Raised Alpha-Fetoprotein Level and its Association with Hepatocellular Carcinoma

Objective: To evaluate raised alpha feto-protein levels for socio-demographic and clinicopathological features in hepatocellular carcinoma. Study Design: Cross-sectional study. Place and Duration of Study: Department of Medical Oncology, Jinnah Postgraduate Medical Center, Karachi Pakistan, from Jan 2019 to Jan 2020. Methodology: Two hundred and thirty-six patients of age more than 20 years, of either gender diagnosed with hepatocellular carcinoma were included. Detailed demographic data, information regarding addiction and medical history were collected. According to The National Comprehensive Cancer Network, Hepatocellular carcinoma was diagnosed using a multiphasic liver protocol CT scan with intravenous contrast. The alpha-fetoprotein levels were checked after confirmation of hepatocellular carcinoma on a multiphasic CT scan. The cut-off value for elevated alpha feto-protein was ≥20 ng/mL. Results: The median alpha protein levels were reported as 411 ng/mL. About 183(78%) patients had elevated alpha protein levels. In univariate analysis, age, gender, diabetes mellitus, hepatitis B, hepatitis C, portal vein thrombosis, number of lesions, cirrhotic liver, features of portal hypertension, anti-viral treatment status, cigarette smoking, and segment of the liver showed a statistically significant relationship with elevated alpha protein levels (p&lt;0.05). On the multivariate model, age, hepatitis C, number of lesions, portal vein thrombosis, and Child Pugh score showed statistically significant association with elevated alpha protein (p&lt;0.05). Conclusions: The elevated alpha protein levels level was found to be higher among hepatocellular carcinoma and associated with age, hepatitis C, number of lesions, portal vein thrombosis and Child Pugh score.

Single-cell analysis reveals HBV-specific PD-1+CD8+ TRM cells in tumor borders are associated with HBV-related hepatic damage and fibrosis in HCC patients

Immune checkpoint blockade (ICB) treatment of hepatocellular carcinoma (HCC) patients with hepatitis B virus (HBV) infection may activate viral-specific T cells to attack HBV infected hepatocytes and thus induce immune-related liver injury. Therefore, it is important to deeply understand the impacts of HBV infection on HCC immune microenvironment in order to better design effective immunotherapies for HBV+ (HBV infected) HCC patients. Here, We performed cytometry by time-of-flight (CyTOF) analyses to characterize the distinct immune compositions of HCC tumors, tumor borders, and their associations with HCC/HBV related clinical characteristics. We identified 31 distinct immune clusters and found significant associations between immune signatures with clinicopathological features of HCC. We further revealed the HBV infection had more effects on shaping immune compositions in tumor borders than in tumors, with the significant enrichment of HBV-specific PD-1+CD8+ tissue-resident memory T (TRM) cells in tumor borders of HBV+ patients. We confirmed this subset with a more exhausted phenotype and respond more actively under anti-PD-L1 treatment, suggesting its involvement in immune-related liver injury induced by ICB treatment to HBV+ HCC patients. Our study shows it may be necessary to consider antiviral prophylaxis for HBV+ HCC patients receiving ICB treatment.

A Clinicopathological Study of Hepatocellular Carcinoma: A Cross Sectional Study

The purpose of the present study was to find out the clinicopathological characteristics of Hepatocellular Carcinoma (HCC) patients. All the clinically suspected patients were recruited as per inclusion and exclusion criteria. The relevant socio-demographic characteristics, clinical findings as well as the physical examination were performed after talking written consent from all the study subjects. The ultrasonography was performed to all the patients. After that, the patients were sent to the department of pathology for histopathological examination. The descriptive cross-sectional study was carried out in the Department of Oncology of National Institute of Cancer Research and Hospital (NICRH), Dhaka, Bangladesh from July 2014 to June 2015 for a period of 12 months. Total sample size was 52 in this study and age distribution of HCC was found from 25 years to 97 years to with the mean age 50.57 ± 12.09 years. Males were predominant (78.0%), male and female ratio was 3.72:1. The common presenting features of HCC were abdominal pain and swelling, fever and jaundice; viral marker was positive in 86.5% of patients (HBsAg-67.3%, Anti HCV-19.2%) with normal tumor marker alpha-fetoprotein (AFP) in 69% of the patients. Okuda staging shows 82.7% patients within stage I and Stage II and performance status, 38.5% patients were unable to carry out normal activity. Sonological findings revealed 69.2% patients had ≤2 cm tumor size, 88.4% had ascites lastly splenomegaly was present among 86.5% respondents.

Clinicopathological Features of Hepatocellular Carcinoma with Metabolic Risk Factors.

This study aims to explore the pathological characteristics of metabolic-related hepatocellular carcinoma (HCC) and its correlation with metabolic factors. Fifty-one patients with liver cancer of unknown causes were enrolled. Biopsy of the liver and staining of the liver tissues with hematoxylin-eosin as well as special and immunohistochemical stains were performed. The histological subtypes of HCC were diagnosed based on the WHO Classification of Malignant Hepatocellular Tumors. The NAFLD activity score system was adopted for assessing the surrounding non-neoplastic liver tissues. Of the total, 42 (82.4%) patients were diagnosed with HCC, 32 had metabolic risk factors, 20 patients met the diagnostic criteria of the metabolic-associated fatty liver disease (MAFLD)-related HCC, and 40.6% (13/32) had liver cirrhosis. The incidence of cirrhosis (p = 0.033) and diabetes mellitus type 2 (p = 0.036) in patients with MAFLD-related HCC was notably higher than that in HCC patients with only metabolic risk factors. Among the 32 HCC cases with metabolic risk factors, trabecular type was the most prevalent, followed by steatohepatitis type, scirrhous type, solid type, pseudoglandular type, clear-cell type, and macrotrabecular type. The degree of tumor cells' swelling and ballooning was found to be positively related to the degree of fibrosis in the surrounding liver tissues (p = 0.011) as well as the proportion of cirrhosis (p = 0.004). Moreover, the degree of fibrosis in the surrounding liver tissues showed a negative correlation with the levels of serum cholesterol (p = 0.002), low-density lipoprotein (p = 0.002), ApoA1 (p = 0.009), ApoB (p = 0.022), total protein (p = 0.015), WBC count (p = 0.006), and PLT count (p = 0.015). Pathological characteristics of the tumor and adjacent non-neoplastic liver tissues of HCC with metabolic risk factors were found to be correlated with metabolic abnormalities.

Abstract 3305: Clinical significance of circZKSCAN1 RNA in human hepatocellular carcinoma

Abstract Circular RNAs (CircRNAs) are type of noncoding RNAs without 5’ caps and 3’ tails that has been created by back splicing of mRNA. Recently, circRNAs are identified in many types of cancers, and its function has been elucidated as multiple miRNAs sponge. Hepatocellular carcinoma (HCC) is the most common type of malignancies. The incidence and mortality of HCC have been on the rise in recent years. Thus, it is necessary to identify further molecular mechanisms of HCC initiation and progression. In this study, we aim to investigate the clinical relevance of circRNAs encoded by the ZKSCAN1 (Zinc finger protein with KRAB and SCAN domains 1) gene in HCC.We analyzed clinical specimens from 100 pairs of HCC and corresponding normal liver (NL) tissues. Total RNAs were isolated from clinical tissues using qiagen kit. CircRNAs (circZKSCAN1) derived from ZKSCAN1 gene. The expression levels were determined by quantitative real-time PCR (qRT-PCR), and its expression was normalized with GAPDH. In addition, we analyzed the correlation between circZKSCAN1 expression and various clinicopathological features of HCC patients.CircZKSCAN1 expression was significantly down-regulated in HCC tissues compared to corresponding NL tissues (P&amp;lt;0.001). In HCC patients, circZKSCAN1 expression was gradually suppressed according to state of malignant progression (P&amp;lt;0.010). Further correlation analysis showed that circZKSCAN1 expression was significantly associated with T-stage (P=0.009), TNM stage (P=0.002), BCLC stage (P=0.0467), and survival (P&amp;lt;0.001).Conclusively, we have determined clinical significances of circZKSCAN1 expression in HCC, which may provide clinical evidence for the potential of circZKSCAN1 as novel markers for diagnosis and predicting prognosis in HCC patients. Citation Format: Minji Bang, Gyeonghwa Kim, Eun Hwangbo, Mi Yeon Jeon, Keun Hur. Clinical significance of circZKSCAN1 RNA in human hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3305.

LincRNA ZNF529-AS1 inhibits hepatocellular carcinoma via FBXO31 and predicts the prognosis of hepatocellular carcinoma patients

BackgroundInvasion and metastasis of hepatocellular carcinoma (HCC) is still an important reason for poor prognosis. LincRNA ZNF529-AS1 is a recently identified tumour-associated molecule that is differentially expressed in a variety of tumours, but its role in HCC is still unclear. This study investigated the expression and function of ZNF529-AS1 in HCC and explored the prognostic significance of ZNF529-AS1 in HCC.MethodsBased on HCC information in TCGA and other databases, the relationship between the expression of ZNF529-AS1 and clinicopathological characteristics of HCC was analysed by the Wilcoxon signed-rank test and logistic regression. The relationship between ZNF529-AS1 and HCC prognosis was evaluated by Kaplan‒Meier and Cox regression analyses. The cellular function and signalling pathways involved in ZNF529-AS1 were analysed by GO and KEGG enrichment analysis. The relationship between ZNF529-AS1 and immunological signatures in the HCC tumour microenvironment was analysed by the ssGSEA algorithm and CIBERSORT algorithm. HCC cell invasion and migration were investigated by the Transwell assay. Gene and protein expression were detected by PCR and western blot analysis, respectively.ResultsZNF529-AS1 was differentially expressed in various types of tumours and was highly expressed in HCC. The expression of ZNF529-AS1 was closely correlated with the age, sex, T stage, M stage and pathological grade of HCC patients. Univariate and multivariate analyses showed that ZNF529-AS1 was significantly associated with poor prognosis of HCC patients and could be an independent prognostic indicator of HCC. Immunological analysis showed that the expression of ZNF529-AS1 was correlated with the abundance and immune function of various immune cells. Knockdown of ZNF529-AS1 in HCC cells inhibited cell invasion and migration and inhibited the expression of FBXO31.ConclusionZNF529-AS1 could be a new prognostic marker for HCC. FBXO31 may be the downstream target of ZNF529-AS1 in HCC.

Identification of oncogenes and tumor-suppressor genes with hepatocellular carcinoma: A comprehensive analysis based on TCGA and GEO datasets.

Aim: Existing targeted therapies for hepatocellular carcinoma (HCC) are resistant and have limitations. It is crucial to find new HCC-related target genes. Methods: RNA-sequencing data of HCC were gathered from The Cancer Genome Atlas and Gene Expression Omnibus datasets. Initially, differentially expressed genes between normal and tumor tissues were identified from four Gene Expression Omnibus datasets, GSE36376, GSE102079, GSE54236, and GSE45267. GO terms and KEGG pathway enrichment analyses were performed to explore the potential biological functions of differentially expressed genes. A PPI network was constructed by using the STRING database, and up-regulated and down-regulated hub genes were defined through 12 topological approaches. Subsequently, the correlation bounded by up-regulated genes and down-regulated genes in the diagnosis, prognosis, and clinicopathological features of HCC was analyzed. Beyond a shadow of doubt, the key oncogene PBK and tumor suppressor gene F9 were screened out, and the specific mechanism was investigated through GSEA enrichment analysis and immune correlation analysis. The role of PBK in HCC was further verified by western blot, CCK8, transwell, and tube formation experiments. Results: CDCA5, CDC20, PBK, PRC1, TOP2A, and NCAPG are good indicators of HCC diagnosis and prognosis. The low expressions of F9, AFM, and C8B indicate malignant progression and poor prognosis of HCC. PBK was found to be closely related to VEGF, VEGFR, and PDGFR pathways. Experiments showed that PBK promotes HCC cell proliferation, migration, invasion, and tube formation in HUVEC cells. F9 was negatively correlated with the degree of immune infiltration, and low expression of F9 suggested a poor response to immunotherapy. Conclusion: The role of HCC-related oncogenes and tumor-suppressor genes in diagnosis and prognosis was identified. In addition, we have found that PBK may promote tumor proliferation through angiogenesis and F9 may be a predictor of tumor immunotherapy response.

Evaluation of transcriptomic molecular classification, biological behavior, and clinicopathological features in hepatocellular carcinoma

ABSTRACT Background Studies in France, Korea, and Singapore found that G1-G6 transcriptomes are involved in hepatocellular carcinoma (HCC) carcinogenesis. However, the suitability of this method in Chinese HCC patients has remained unknown. Methods The correlation between the G1–G6 molecular classification and clinicopathological features were analyzed in 107 Chinese HCC patients through the retrospective cohort study. RNA sequencing and bioinformatics analysis were performed to screen related targets and molecular signaling pathways. Results We found that the G1–G3 subgroups were associated with high serum alpha-fetoprotein (AFP) level, high copy number of hepatitis B virus (HBV) DNA, complex histopathological structure, macrovascular invasion. The G1 subgroup was mainly related to liver cancer stemness, and G3 subgroup showed the worst prognosis. The G5 and G6 subgroups were associated with activation of the Wnt/β-catenin pathway. Compared with the G4–G6 group, the G1–G3 group showed significantly higher expression levels of regenerating family member 1 beta (REG1B), regenerating family member 3 gamma (REG3G), and inositol 1,4,5-trisphosphate receptor type 1 (ITPR1), and enriched calcium signaling pathway. Conclusions This study enhances our understanding of the heterogenicity of China HCC and indicates that the G1–G6 signatures can be used to identify predictive biomarkers against HCC patients in China.

The Genomic and Proteomic Profiles of NTRK Genes and Trk Receptors in Liver Hepatocellular Carcinoma.

The neurotrophic tyrosine kinase (NTRK) gene family includes NTRK1, NTRK2, and NTRK3, which encode tropomyosin receptor kinases TrkA, TrkB, and TrkC, respectively. This study aimed to initially assess the genomic and proteomic profiles of NTRK genes and Trk receptors in liver hepatocellular carcinoma (LIHC). The ONCOMINE, UALCAN, GEPIA, cBioPortal, FusionGDB, SurvivalMeth, and the Human Protein Atlas databases were searched for NTRK gene expression and protein data in LIHC. Immunohistochemistry was used to detect pan-Trk expression across a commercial microarray containing 96 hepatocellular carcinoma (HCC) and 94 para-cancerous tissue spots. A modified histological score (H-score) with a maximum score of 300 was used to quantify immunohistochemical staining for pan-Trk. Student's t- and chi-square tests were the main statistical analyses used. The transcriptional levels of NTRK genes in LIHC were not significantly different from healthy controls. Using UALCAN and GEPIA, only high expression of NTRK2 was significantly associated with longer disease-free survival (P = 0.004). The alteration frequencies were low (7% in NTRK1, 1.7% in NTRK2, and 2% in NTRK3). The methylation levels of NTRK genes were all significantly different as analyzed by UALCAN; the high-risk group displayed an unfavorable prognosis compared with the low-risk group for NTRK1 (P = 0.033) and NTRK3 (P = 0.005). The median H-score of pan-Trk in HCC and para-cancerous tissues was not statistically different (186.31 ± 23.86 and 192.38 ± 21.06, P = 0.065). No differences were observed in clinicopathological features of HCC with the median H-score for pan-Trk expression (p > 0.05). The survival rate of patients with pan-Trk expression was also not significantly different. The alteration frequency was low in NTRK genes, including gene fusion and methylation levels. Therefore, pan-Trk expression in HCC tissue has limited value in clinicopathological features and prognosis.

The role of UCA1 and WRAP53 in diagnosis of hepatocellular carcinoma: A single-center case-control study.

Hepatocellular carcinoma (HCC) prognosis heavily depends on early diagnosis. We aimed to determine the role of serum urothelial carcinoma-associated 1 (UCA1) and wd repeat containing antisense to TP53 (WRAP53) as diagnostic tools of HCC. A case-control study including 90 subjects (30 patients having HCC, 30 patients having liver cirrhosis without HCC and 30 healthy controls) was performed. In all participants, the serum levels of UCA1 and WRAP53 were assessed by quantitative real-time polymerase chain reaction together with serumαa-fetoprotein (AFP). Serum levels of both UCA1 and WRAP53 were upregulated in patients with HCC being significantly higher than in patients with liver cirrhosis and healthy control (p < 0.001). They were also correlated with some clinicopathological characteristics of HCC. Using the receiver operating curve, both UCA1 and WRAP53 showed higher diagnostic performance for HCC (AUC = 0.9, 73.3% sensitivity, 100% specificity and AUC = 0.85, 63.3% sensitivity, 80% specificity respectively) and their combination with AFP resulted in improved sensitivity and specificity (AUC = 0.97, 90% sensitivity, 100% specificity). Serum UCA1 and WRAP53 have the potential to be used alone, or in combination or with AFP, as diagnostic non-invasive biomarkers for HCC with accepted sensitivity and specificity. This study has been registered in clinicaltrials.gov with clinical trial registration number NCT05088811.

Clinical and prognostic significance of CCPG1 in hepatocellular carcinoma.

This study aimed to examine the clinical and prognostic significance of cell-cycle progression gene 1 (CCPG1) in hepatocellular carcinoma (HCC). We firstly analyzed CCPG1 expression in various cancers using The Cancer Genome Atlas and the Genotype-Tissue Expression project databases. The relative expression levels of CCPG1 were determined in 164 paired HCC and adjacent tissues using immunohistochemistry. The correlation between CCPG1 and clinicopathological characteristics of HCC was analyzed. Cox proportional models were used to identify the prognostic factors for overall survival (OS) and disease-free survival (DFS). The expression of CCPG1 was lower in HCC tissues than in adjacent non-tumor liver tissues. The expression of CCPG1 was significantly correlated with tumor number (p = 0.02) and tumor differentiation (p = 0.04) in HCC. Lower expression of CCPG1 in HCC patients was associated with poor OS and DFS (p < 0.01). Relative low expression of CCPG1 in HCC is significantly correlated with the poor prognosis of HCC patients after surgical resection, suggesting its possible role as a potential prognostic marker for HCC.

Comprehensive analysis of prognostic value and immune infiltration of IAPs family in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a malignant tumor with high morbidity and mortality rates. The inhibitors of apoptosis (IAP) family act as oncogenes in various tumor types; however, their functions in HCC remain unclear. Here, we used integrated bioinformatics analysis and experimental verification to assess the expression and the prognostic and clinical value of the IAP family in HCC. Using the University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) and the Tumor Immune Estimation Resource (TIMER), we analyzed the expression profiles of IAP family members in HCC tissue, normal tissues, and in patients with different stages and grades of HCC. We further verified the expression level of BIRC2 in 25 HCC samples and matched adjacent normal tissues using quantitative real-time PCR (qRT-PCR), and analyzed its correlation with the marker gene of T-helper type 1 cells (Th1)-STAT1. Meanwhile, the association between BIRC2 and the immunotherapeutic response or immunomodulators was confirmed using the Biomarker Exploration of Solid Tumors (BEST) database. The results showed that NAIP, BIRC2, BIRC3, XIAP, BIRC5, and BIRC6 mRNAs were overexpressed in HCC. The clinical stages, pathological grades, and other clinicopathological features of HCC were closely related to the expression levels of the IAP family members, especially the BIRC2 and BIRC5, which were found to be potential prognostic biomarkers for HCC. Expression of the IAPs was strongly associated with immune cell infiltration. Based on the infiltrative status of various immune cells, HCC patients with high BIRC2 and BIRC5 expression demonstrated poor overall survival (OS) rates. In patients with HCC, BIRC2 expression was noticeably elevated. Concurrently, the expression levels of BIRC2 and STAT1 showed a favorable correlation. BEST database analysis revealed that BIRC2 was a negative predictor of responsiveness to anti-programmed cell death ligand 1 (PD-L1)/cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibitor treatment in HCC, and BIRC2 mRNA expression levels were positively correlated with the expression levels of the immune checkpoint genes programmed cell death protein 1 (PD-1), PD-L1, and CTLA-4 in HCC. Consequently, the IAP family may play a role in carcinogenesis and cancer-immune system interactions in HCC. Our results demonstrate that IAP family members may be viable predictive biomarkers and therapeutic targets for HCC.

The Role of LINC01564, RAMS11, CBX4 and TOP2A in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common histologic type of primary liver cancers worldwide. Hepatitis C virus (HCV) infection remains a major risk factor for chronic liver disease, cirrhosis, and HCC. To understand the molecular pathogenesis of HCC in chronic HCV infection, many molecular markers are extensively studied, including long noncoding RNAs (lncRNA). To evaluate the expression levels of lncRNAs (LINC01564, RAMS11), CBX4, and TOP2A in patients with chronic HCV infection and patients with HCC on top of chronic HCV infection and correlate these levels with the clinicopathological features of HCC. One hundred and fifty subjects were enrolled in this study and divided into three groups: group I included 50 patients with HCC on top of chronic hepatitis C (CHC), group II included 50 patients with CHC only, and group III included 50 healthy individuals as a control group. LncRNAs relative expression level was determined by RT-PCR. lncRNA (LINC01564, RAMS11), CBX4, and TOP2A relative expression levels were upregulated in both patient groups compared to controls (p &lt; 0.001*), with the highest levels in the HCC group compared with the CHC group. Additionally, these levels were significantly positively correlated with the clinicopathological features of HCC. The lncRNA (LINC01564, RAMS11), CBX4, and TOP2A relative expression levels were upregulated in CHC patients-in particular, patients with HCC. Thus, these circulatory lncRNAs may be able to serve as promising noninvasive diagnostic markers for HCC associated with viral C hepatitis.

Generation of multicellular tumor spheroids with micro-well array for anticancer drug combination screening based on a valuable biomarker of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a highly malignant tumor with a poor prognosis. More than 30% of patients with diagnosed HCC have abnormally high expression of fibroblast growth factor receptor 4 (FGFR4). Currently, clinical trials for a variety of FGFR4-specific inhibitors have started. However, the effect of these inhibitors is not ideal, and it is necessary to find a drug combination to synergistically exert anti-tumor effects. We found strong correlations between FGFR4 and HCC clinicopathological characteristics in the present study. After grouping patients according to FGFR4 expression, the key gene signatures were inputted the drug-gene related databases, which predicted several potential drug candidates. More importantly, to achieve the reliable and high throughput drug cytotoxicity assessment, we developed an efficient and reproducible agarose hydrogel microwells to generate uniform-sized multicellular tumor spheroids, which provide better mimicry of conventional solid tumors that can precisely represent anticancer drug candidates' effects. Using high content screening, we quickly evaluated the enhanced anti-tumor effects of these combinations. Finally, we demonstrated that Parthenolide is a potential drug that can significantly enhance the clinical efficacy of FGFR4 receptor inhibitors. In general, we offered a new therapeutic way for FGFR4 positive HCC patients.

Circulating tumor cell associated white blood cell cluster as a biomarker for metastasis and recurrence in hepatocellular carcinoma.

Recently, an in vivo study demonstrated that circulating tumor cell-associated white blood cell (CTC-WBC) cluster possess much greater potential than single CTCs. We aim to explore the correlation between the CTC-WBC cluster and the clinicopathological characteristics of hepatocellular carcinoma (HCC) patients to seek novel biomarkers for HCC metastasis and recurrence. We retrospectively analyzed 136 HCC patients from October 2014 to March 2020 who received CTC tests using the CanPatrol CTC enrichment technique. The correlation between the clinical features and total CTCs, EMT-CTCs, and CTC-WBC cluster were analyzed by a chi-square test. The ROC curves were simulated for evaluating the diagnostic performance of CTC parameters in HCC metastasis. Patients were followed up from February 2015 to November 2021, and the relapse-free survival (RFS) was analyzed using the Kaplan-Meier curve. A total of 93.4% (127/136) and 31.6% (43/136) of HCC patients had detectable CTCs and CTC-WBC clusters. Baseline CTC-WBC cluster was closely correlated with microvascular invasion, portal vein tumor thrombus, and extrahepatic metastasis in pre-treatment HCC patients (P <0.05). The simulated ROC curves presented an AUC of 0.821 for the CTC-WBC cluster (sensitivity of 90.0% and specificity of 93.7%) in discriminating metastasis from non-metastatic HCC, which was higher than that for total CTCs (0.718) and EMT-CTCs (0.716). Further follow-up analysis showed that compared to the CTC-WBC cluster negative group (<1/5ml), patients in the CTC-WBC cluster positive group (≥1/5ml) presented an increased relapse ratio (60.0% versus 17.9%) and shorter RFS (22.9 versus 53.8 months). Dynamic analysis of CTCs parameters showed that total CTC level, EMT-CTCs proportion, and CTC-WBC cluster were decreased after microwave ablation treatment, while CTC-WBC cluster increased on average 10 months in advance of imaging (MRI) diagnosed recurrence. The CTC-WBC cluster is a promising biomarker for the metastasis diagnosis and prognosis of HCC metastasis. Dynamic monitoring of the CTC-WBC cluster is an effective method for early detection and intervention of HCC recurrence and metastasis.

DLGAP4 acts as an effective prognostic predictor for hepatocellular carcinoma and is closely related to tumour progression

Disc large associated protein 4 (DLGAP4) plays an important role in neurological diseases, but the role and mechanism of DLGAP4 in hepatocellular carcinoma (HCC) remain unclear. In this study, the prognostic effect of DLGAP4 on HCC patients was investigated by means of bioinformatics. The correlation of DLGAP4 expression with the prognosis of HCC patients was evaluated by TCGA data analysis, and the correlation between DLGAP4 expression and the clinical characteristics of HCC patients was evaluated by the Wilcoxon signed rank test and logistic regression analysis. Kaplan‒Meier and Cox regression methods were used to assess the effect of DLGAP4 expression level on overall survival, and nomograms were used to illustrate the correlation between DLGAP4 gene expression and HCC risk. The genes related to DLGAP4 in HCC were screened, and GO/KEGG enrichment analysis was performed. Furthermore, in vitro and in vivo experiments were conducted to detect the effect of DLGAP4 expression on the proliferation, migration and metastasis of HCC cells. We also examined the effect of DLGAP4 expression on enriched pathway proteins to explore the possible mechanism. The expression levels of DLGAP4 were significantly higher in HCC cell lines and tissue samples than in normal liver cell lines and tissues. The expression of DLGAP4 was significantly associated with clinical characteristics. Survival analysis showed that high expression of DLGAP4 was associated with a poor prognosis in HCC. Multivariate analysis showed that high expression of DLGAP4 was an independent risk factor affecting the overall survival rate in HCC patients. By means of ROC curve analysis and nomograms, we determined the value of DLGAP4 expression in the diagnosis and prognosis evaluation of HCC. GO/KEGG enrichment analysis showed that the PPAR signalling pathway was differentially enriched in patients with high expression of DLGAP4. According to in vitro and in vivo experiments, DLGAP4 knockdown inhibited the proliferation and metastasis of HCC cells and decreased the expression of PPARβ/δ protein. In contrast, overexpression of DLGAP4 promoted the proliferation and metastasis of HCC cell, and increased the expression of PPARβ/δ protein.In contrast, overexpression of DLGAP4 promoted the proliferation and metastasis of HCC cells and increased the expression of PPARβ/δ protein. The results show a close correlation between DLGAP4 expression and clinicopathological features of HCC, and DLGAP4 can be used as a prediction biomarker of HCC.

Programmed death-ligand 1 (PD-L1) polymorphisms as predictive biomarkers for the development of liver cirrhosis and hepatocellular carcinoma in HCV Egyptian patients

BackgroundConsidering the immune evasion role of programmed death-ligand 1 (PD-L1) in cancer development, its genomic variations might be closely associated with disease development and cancer risks. Accordingly, this study was performed to investigate how the PD-L1 gene polymorphisms affect the susceptibility to hepatitis C virus (HCV)-induced liver cirrhosis and cancer development in the Egyptian population. MethodologyTwo single nucleotide polymorphisms of the PD-L1 gene; rs2297136 (A > G) and rs4143815 (C > G), were studied in 50 HCV, 51 liver cirrhosis, and 52 hepatocellular carcinoma (HCC) patients as well as 50 healthy subjects using real-time PCR. ResultsThe frequencies of PD-L1 rs2297136 AA and rs4143815 GG genotypes were significantly higher in the liver cirrhosis than the control and HCV groups. The rs4143815 CG and GG genotypes were linked to a higher risk of developing HCC and were positively associated with the clinicopathological features of HCC. ConclusionsThe PD-L1 rs2297136 AA and rs4143815 GG genotypes increase the susceptibility to liver cirrhosis. The rs4143815 CG and GG genotypes are positively associated with HCC risk and its clinicopathological characteristics. Therefore, HCV patients carrying the PD-L1 rs4143815 G-allele should be followed up on a regular basis to allow for early HCC management.

EIF2S2 is a novel independent prognostic biomarker and correlated with immune infiltrates in hepatocellular carcinoma

Background: Hepatocellular carcinoma (HCC) is a highly malignant disease with poor prognosis. It is urgent to find effective biomarkers. Eukaryotic Translation Initiation Factor 2 Subunit Beta (EIF2S2) is a subunit of heterotrimeric G protein EIF2, and its function is still unclear. We studied the role of EIF2S2 in the malignant progression of liver cancer and its relationship with immune infiltration. Methods: Download the RNA expression and clinical information of EIF2S2 from the Cancer Genome Atlas (TCGA) database, analyze the relationship between the expression of EIF2S2 and the prognosis and clinicopathological characteristics of HCC, analyze the differential genes by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and tumor related immune infiltrating cells. The Protein expression level of EIF2S2 was obtained from Human Protein Atlas (HPA) databases. The relationship between EIF2S2 expression and immune infiltrates in HCC was analyzed on TIMER 2.0. The data processing analysis based on R language. Drug Sensitivity data from Genomics of Drug Sensitivity in Cancer (GDSC). Results: EIF2S2 is highly expressed in HCC patients and is associated with poor prognosis. The expression of EIF2S2 was also correlated with age, clinical stage and pathological grade. Univariate and multivariate COX regression analysis showed that EIF2S2 was an independent risk factor for survival. The receiver operating characteristic (ROC) curve of EIF2S2 also confirmed the diagnostic value of EIF2S2 in HCC patients. Through GO and KEGG enrichment analysis, EIF2S2 expression was found to be closely related to some immune pathways. The expression of EIF2S2 was correlated with memory B cell, plasma B cell, CD8+ T cell, CD4+ resting memory T cell and the expression of some immune checkpoints, such as PDCD1, TIGIT and CTLA-4. It is also more sensitive to paclitaxel, sunitinib and other drugs. Conclusion: This study shows that EIF2S2 can be used as a prognostic factor for HCC, which is closely related to immune infiltration and immune checkpoints, and may play a potential regulatory role in predicting drug sensitivity.