Study on the expression of TOP2A in hepatocellular carcinoma and its relationship with patient prognosis

Background Hepatocellular carcinoma (HCC) is a primary liver cancer with a high mortality rate. However, the molecular mechanism of HCC formation remains to be explored and studied. Objective To investigate the expression of TOP2A in hepatocellular carcinoma (HCC) and its prognosis. Methods The data set of hepatocellular carcinoma was downloaded from GEO database for differential gene analysis, and hub gene was identified by Cytoscape. GEPIA was used to verify the expression of HUB gene and evaluate its prognostic value. Then TOP2A was selected as the research object of this paper by combining literature and clinical sample results. Firstly, TIMER database was used to study TOP2A, and the differential expression of TOP2A gene between normal tissues and cancer tissues was analyzed, as well as the correlation between TOP2A gene expression and immune infiltration of HCC cells. Then, the expression of top2a-related antibodies was analyzed using the Human Protein Atlas database, and the differential expression of TOP2A was verified by immunohistochemistry. Then, SRTING database and Cytoscape were used to establish PPI network for TOP2A and protein–protein interaction analysis was performed. The Oncomine database and cBioPortal were used to express and identify TOP2A mutation-related analyses. The expression differences of TOP2A gene were identified by LinkedOmics, and the GO and KEGG pathways were analyzed in combination with related genes. Finally, Kaplan–Meier survival analysis was performed to analyze the clinical and prognosis of HCC patients. Results TOP2A may be a new biomarker and therapeutic target for hepatocellular carcinoma.

Combination of Tertiary Lymphoid Structure and Neutrophil-to-Lymphocyte Ratio Predicts Survival in Patients With Hepatocellular Carcinoma

BackgroundHepatocellular carcinoma (HCC) is the most common pathological type of primary liver cancer. The lack of prognosis indicators is one of the challenges in HCC. In this study, we investigated the combination of tertiary lymphoid structure (TLS) and several systemic inflammation parameters as a prognosis indicator for HCC.Materials and MethodsWe retrospectively recruited 126 postoperative patients with primary HCC. The paraffin section was collected for TLS density assessment. In addition, we collected the systemic inflammation parameters from peripheral blood samples. We evaluated the prognostic values of those parameters on overall survival (OS) using Kaplan-Meier curves, univariate and multivariate Cox regression. Last, we plotted a nomogram to predict the survival of HCC patients.ResultsWe first found TLS density was positively correlated with HCC patients’ survival (HR=0.16, 95% CI: 0.06 − 0.39, p < 0.0001), but the power of TLS density for survival prediction was found to be limited (AUC=0.776, 95% CI:0.772 − 0.806). Thus, we further introduced several systemic inflammation parameters for survival analysis, we found neutrophil-to-lymphocyte ratio (NLR) was positively associated with OS in univariate Cox regression analysis. However, the combination of TLS density and NLR better predicts patient’s survival (AUC=0.800, 95% CI: 0.698-0.902, p < 0.001) compared with using any single indicator alone. Last, we incorporated TLS density, NLR, and other parameters into the nomogram to provide a reproducible approach for survival prediction in HCC clinical practice.ConclusionThe combination of TLS density and NLR was shown to be a good predictor of HCC patient survival. It also provides a novel direction for the evaluation of immunotherapies in HCC.

Heterogeneity, Inherent and Acquired Drug Resistance in Patient-Derived Organoids Models of Primary Liver Cancer

To screen for sensitive drugs for recurrent primary liver cancer (PLC) and elucidate the mechanisms underlying inherent and acquired drug resistance, we established a platform of organoids, organoids-derived xenograft (ODX) mouse models, and patient-derived xenograft (PDX) mouse models of primary liver cancer (PLC). Fifty-two organoids were established from 153 PLC patients. Establishing organoids of hepatocellular carcinoma (HCC) displayed a trend toward a higher success rate than establishing PDX (29.0% vs. 23.7%) and took a shorter duration (13.0 ± 4.7 vs. 25.1 ± 5.4 days, P=2.28×10−13) than establishing PDX models. Larger tumor, vascular invasion, and advanced stage were significantly associated with successful establishment of organoids and PDX in HCC. Organoids and ODX recapitulated PLC histopathological features but enriched more aggressive cell types. PLC organoids were mostly resistant to lenvatinib in vitro but sensitive in ODX model, indicating innate immunity plays a role. Acquired sorafenib-resistant HCC organoids were generated via 3–5 months of induction. RNA-sequencing indicated that stemness– and epithelial–mesenchymal transition (EMT)–related gene sets were upregulated, whereas liver development– and liver specific molecule–related gene sets were downregulated, in acquired sorafenib-resistant organoids. Targeting mTOR signaling pathway was effective in treating acquired sorafenib-resistant HCC, possibly via inducing phosphorylated S6 kinase. Genes upregulated in acquired sorafenib-resistant HCC organoids were often associated with unfavorable prognosis. Conclusively, HCC organoids perform better than PDX for drug selection. Acquired sorafenib resistance in organoids promotes HCC aggressiveness via facilitating the stemness, retrodifferentiation, and EMT. Phosphorylated S6 kinase might be predictive for drug resistance in HCC.

Assessment of Plasma Vitronectin as Diagnostic and Prognostic Marker of Hepatocellular Carcinoma in Patients with Hepatitis C Virus Cirrhosis

Background: hepatitis C is an inflammatory liver disease caused by the hepatitis C infection (HCV), and without treatment, almost 50% will progress to liver cirrhosis. Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer and the fourth leading cause of cancer-related mortality. Aim of the study: the objective of this study was to evaluate the serum level of vitronectin (VTN) compared to AFP and determine their role as diagnostic and prognostic markers of HCV-related liver diseases. Subject and Methods: this study involved 52 HCV patients from which 26 patients were cirrhotic, and 26 patients had HCC (on top of hepatitis C virus-related cirrhosis) plus 10 healthy people as a control group. It was carried out in Gastroenterology and Hepatology Unit, Internal Medicine Department, Zagazig University Hospitals, Egypt. All individuals in this study were subjected to physical examination, full history taking, liver function tests, assessment of serum levels of Vitronectin (VTN) and alpha-fetoprotein (AFP) before and after the intervention within three months. Results: serum level of vitronectin increased significantly in cirrhosis patients and HCC patients than controls (p = 0.0041), (p < 0.001), respectively, and in HCC than cirrhosis patients (p < 0.001). Significant positive correlations were observed between levels of serum VTN and AFP in all HCV patients as well as cirrhotic patients (p < 0.001, p = 0.011, respectively). On the contrary, VTN and AFP didn’t show a significant correlation in HCC patients’ group. Moreover, the median serum level of VTN decreased significantly after treatment in patients with HCC (p < 0.001). At cut-off 38.5 ng/mL for AFP it shows sensitivity 80.8%, specificity 76.9% to differentiate HCC from cirrhosis cases. While VTN shows 84.6% sensitivity, 96.2% specificity at cut-off 26.5 μg/mL. Regarding clinicopathological characteristics and VTN levels, half of patients were stage B, 63.9% had tumor size >3 cm, 84.6% had more than one focal lesion. Conclusions: these results may allow one to speculate a potential role of Vitronectin in diagnosis and prognosis of HCC on top of cirrhosis related to HCV infection in addition to AFP and US and CT.

Research on Classification of Primary Liver Cancer Syndrome Based on Data Mining Technology

This study is based on the analysis of the status quo of the research on liver cancer syndromes, starting with the clinical objective and true four-diagnosis information of TCM inpatients with primary liver cancer, using computer data mining technology to analyze and summarize the syndrome rules from the bottom to the top. Let the data itself show the essence of liver cancer syndrome. First, with the help of hierarchical cluster analysis, we can understand the general characteristics through the rough preliminary classification of the four-diagnosis information of liver cancer patients. Then, with the help of the emerging and mature hidden structure model analysis in recent years, through data modeling, the classification of common syndromes of liver cancer and the corresponding relationship with the four-diagnosis information are comprehensively analyzed. Finally, considering the inherent shortcomings of implicit structure and hierarchical clustering based on the assumption that there is a unique one-to-one correspondence between the four diagnostic information factors and the class (or hidden class) when classifying, we plan to use factor analysis and joint cluster analysis, as supplementary means to further explore the classification of liver cancer syndromes and the corresponding relationship with the four-diagnosis information.

Relationship Between Fish Oil Use and Incidence of Primary Liver Cancer: Findings From a Population-Based Prospective Cohort Study

Background: N-3 long-chain polyunsaturated fatty acids (LCPUFAs) prevented non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) in studies of mouse models. We examined prospective relationships between fish oil use and risk of primary liver cancer and the major histological subtypes, such as HCC and intrahepatic cholangiocarcinoma (ICC).Methods: We included 434,584 middle-aged and older men and women who were free of cancer at recruitment of the UK Biobank (2006–2010). Information on fish oil use and other dietary habits was collected via questionnaires. Cox proportional hazards models were used to compute the hazard ratio (HR) and 95% CI of liver cancer associated with fish oil use, with adjustment for socio-demographic, lifestyle, dietary, and other clinical risk factors.Results: At baseline, 31.4% of participants reported regular use of fish oil supplements. During a median of 7.8 years of follow-up, 262 incident liver cancer cases were identified, among which 127 were HCC and 110 were ICC cases. As compared with non-users, fish oil users had a significantly 44% (95% CI: 25–59%) lower risk of total liver cancer, and 52% (95% CI: 24–70%) and 40% (95% CI: 7–61%) lower risk of HCC and ICC, respectively. Higher intake of oily fish also was associated with a lower risk of HCC (≥2 vs. &lt;1 serving/week: HR = 0.46; 95% CI: 0.23–0.96; P-trend = 0.027) but not ICC (P-trend = 0.96).Conclusion: Habitual use of fish oil supplements was associated lower risk of primary liver cancer regardless of cancer histological subtypes, potentially supporting a beneficial role of dietary n-3 LCPUFAs in liver cancer prevention.