Serum exosomal miR-1275 as a potential biomarker for the diagnosis and prognostic assessment of hepatocellular carcinoma.

Objectives Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths, due to high morbidity, a low early diagnosis rate, and poor prognosis. It is essential to explore competitive endogenous RNA (ceRNA) arrays for early diagnosis and prognosis of HCC. Methods The original gene expression profiles of differentially expressed lncRNA, miRNA and mRNA in HCC were downloaded from TCGA database. Differentially expressed lncRNA-miRNA and miRNA-mRNA interaction pairs were extracted from miRcode and starBase, a ceRNA network was constructed, and GO annotation and KEGG pathway analyses were performed. Cox regression and Kaplan-Meier survival analysis screening identified core genes in the network associated with HCC survival, centering on miRNA, which were screened using ceRNA arrays. qRT-PCR was used to detect the expression level of key genes in clinical samples. Dual luciferase reporter gene assays were used to verify the target binding relationship among lncRNA, mRNA, and miRNA. ROC curves were used to analyze the diagnostic efficacy of the ceRNA array. Results A total of 8 lncRNAs, 5 miRNAs, and 21 mRNAs were used to construct a ceRNA network. Functional enrichment analysis showed that mRNAs in the ceRNA network were mainly enriched in 14 signaling pathways, especially microRNAs in cancer. Survival analysis showed that lncRNA FOXD2-AS1 and miRNA miR-9-5p were related to the prognosis of HCC, and the targeted binding relationships between mRNAs. STMN1, COL15A1, and CCNE2 and miR-9-5p from the TargetScan, starBase, miRDB, and PicTar databases were reliable. qRT-PCR showed that expression levels of FOXD2-AS1, miR-9-5p, STMN1, COL15A1, and CCNE2 were upregulated in HCC tissues. Dual luciferase reporter assays showed that FOXD2-AS1 and STMN1 had a targeted binding relationship with miR-9-5p, but not with COL15A1 or CCNE2. The area under the curve of the candidate ceRNA array (FOXD2-AS1/miR-9-5p/STMN1/COL15A1/CCNE2) was higher than that of each member and ceRNA combination (FOXD2-AS1/miR-9-5p/STMN1). Conclusions The candidate ceRNA array formed by FOXD2-AS1/miR-9-5p/STMN1/COL15A1/CCNE2 could be a biomarker for early diagnosis and prognosis of HCC.

Background: Circulating exosomal microRNAs (miRNAs) are considered as potentially non-invasive biomarkers for early detection and prognosis of cancers. Due to the lack of highly sensitive and specific molecular markers, a lot of patients with hepatocellular carcinoma are diagnosed in advanced stages. This study aims to explore the expression mode and clinical detection value of serum exosomal miR-34a in HCC, providing new potential targets and theoretical basis for the early diagnosis and prognosis monitoring of hepatocellular carcinoma.Methods: The expression of serum exosomal miR-34a in 60 HCC patients before and after operation and 60 healthy examiners was abstracted and detected by ultracentrifugation and real-time quantitative PCR. Using ROC analysis, Kaplan-Meier survival analysis and Cox regression analysis, the value of serum exosomal miR-34a on diagnosis and prognosis in HCC patients was assessed.Results: The expression level of serum exosomal miR-34a in preoperative patients was reduced significantly comparing with that in healthy examiners and postoperative patients (P<0.01; P<0.05). Moreover, the decrease of serum exosomal miR-34a was correlated significantly with differentiation degree, TNM stage, tumor infiltration depth and lymph node metastasis(P<0.05), but had no statistical differences with gender, age, ALT, AST, viral infection, cirrhosis and tumor size of HCC patients (P>0.05). At the same time, the combination of serum exosomal miR-34a and α-fetoprotein (AFP) showed high capability on diagnosis to distinguish healthy examiners and HCC patients through ROC analysis. The overall survival of patients with lower expression of serum exosomal miR-34a was worse than that of patients with high level expression by Kaplan-Meier survival analysis (P<0.05). Univariate and multivariate Cox regression analysis both showed that serum exosomal miR-34a was independently related to OS.Conclusions: Collectively, serum exosomal miR-34a is significantly down-regulated in HCC patients and might be a novel noninvasive biomarker for diagnosis and prognosis of HCC.

Purpose of ReviewHepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with rising incidence and mortality. Early-stage HCC is often asymptomatic, and the lack of reliable early diagnostic markers leads to late-stage diagnosis with limited treatment options. Current treatment relies on tumour staging and patient status, but accurate staging requires invasive procedures that fail to capture tumour heterogeneity and progression. There is an urgent need for less invasive diagnostic strategies, such as liquid biopsy technologies, which allow for repeated sampling and real-time analysis of tumour dynamics. Liquid biopsies, including circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA), offer the potential to monitor recurrence, metastasis, and treatment responses, potentially transforming HCC clinical management by enabling earlier intervention and personalised treatment strategies.Recent FindingsRecent studies emphasise the potential of ctDNA as a non-invasive biomarker by targeting DNA methylation for early HCC detection, enabling timely intervention and personalised treatment to improve patient outcomes. Comparative analyses have shown that ctDNA mutation testing outperforms alpha-fetoprotein (AFP), with a sensitivity of 85% and a specificity of 92%, compared to 60% sensitivity and 80% specificity for AFP. Additionally, profiling the ctDNA mutation landscape of 100 HCC patients has identified recurrent mutations in genes such as TP53, CTNNB1, and AXIN1.SummaryctDNA appears to be a promising non-invasive biomarker in the clinical management of HCC patients, with the sensitivity and specificity improving by 41.67% and 15% respectively. The ctDNA mutations, particularly those targeting DNA methylation, highlight great potential for precision medicine, critical for early diagnosis and prognosis of HCC.

Heat shock protein-27 and MiR-17-5p are novel diagnostic and prognostic biomarkers for hepatocellular carcinoma in Egyptian patients

Background Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the most common form of primary liver cancer. Aim of the study to study the level of serum vitronectin (VTN) compared to AFP in diagnosis and prognosis of hepatocellular carcinoma on top of HCV-related liver diseases. Patients and Methods This prospective observational study included a total number of 60 subjects who were divided into 4 groups: Group 1: include 10 normal persons. Group 2: included 10 patients who have Hepatitis C Virus infection. Group 3: included 20 cirrhotic patients. Group 4: included 20 patients with HCC (on top of hepatitis C virus related cirrhosis), in which we tested them for vitronectin before first intervention and after intervention within 3 months. Results The mean age of the cases showed high statistically significant difference between the study groups (P &amp;lt; 0.001).There were a total number of 29 males and 31 females with significant difference in the sex distribution between the study groups. 80% of the cases in HCC group were males. This sex distribution can be attributed to high prevalence of risk factors like smoking, DM and HCV in males in addition to possible role of sex hormones. On analyzing laboratory characters of the studied groups, we found statistically significant difference between cirrhosis group and non-cirrhotic groups with low platelets count, high serum creatinine, high INR, lower serum albumin, high bilirubin and higher AST. The median level of AFP in group 4 (HCC patients) was 110 IU/ml which was higher than its median value in the other study groups with high level of significance between the study groups. The median level of vitronectin levels in the different study groups didn’t reveal a statistically significant difference between the different study groups. Serum level of vitronectin in group 3 (cirrhotic patients) has no statistically significant difference between the three subgroups according to child's classification. By the analysis of serum level of AFP and vitronectin level in group IV (HCC patients) before and after treatment, the median level of AFP was significantly lower than its level before intervention, while the decrease in vitronectin level was statistically insignificant after intervention. Conclusions Chronic HCV infection and its serious complicatons specially HCC are still representing a health challenge in Egypt, reflecting wide HCV prevalence and late diagnosis. Serum AFP alone has an unreliable role in HCC surveillance as it has low sensitivity because it may be normal in up to 40% of HCC cases especially early stages of the tumor, and low specificity as its levels may be elevated in conditions other than HCC as cirrhosis or exacerbation of chronic hepatitis or even in some cases of cholangiocarcinoma. AFP is useful in clinical practice in screening and diagnosis of HCC in association with US and CT. According to our study, we can't use Vitronectin alone in diagnosis and prognosis of HCC on top of cirrhosis related to HCV +ve infection. It didn’t reveal a statistically significant difference between the different study groups ,so it may require further study and research.

Tu1042 Post Pancreatectomy Hemorrage Endovascular Management: Single Instution Experience Using Covered Stents

Tu1041 Post-Chemoembolization Pre-Transplant AFP-L3% Is a Useful Biomarker for Predicting HCC Recurrence After Liver Transplantation

BackgroundHepatocellular carcinoma (HCC) is one of the most common malignant tumors of the digestive system and has high morbidity and mortality rates. It is essential to search new biomarkers to improve the accuracy of early HCC diagnosis. Therefore, we evaluated the diagnostic value of prothrombin induced by vitamin K deficiency or antagonist- II (PIVKA-II) as a potential biomarker that complements α-fetoprotein (AFP) in HCC by detecting the serum PIVKA-II levels.MethodsSerum PIVKA-II levels were compared in 168 HCC patients, 150 benign liver disease patients and 153 healthy controls to investigate the PIVKA-II potential to be a HCC biomarker. Receiver operating characteristic curve (ROC) analysis was used to evaluate the value of PIVKA-II in the diagnosis of HCC and its complementary role of AFP. The correlation between serum PIVKA-II levels and clinicopathological characteristics was analyzed to study the value of PIVKA-II in assessing HCC progression and prognosis. Finally, the ability of PIVKA-II in assessing the surgical treatment effects of HCC was studied by comparing the pre- and post-operative serum PIVKA-II levels in 89 HCC patients.ResultsSerum PIVKA-II levels in HCC patients were significantly higher than that in patients with benign liver disease and healthy controls. The PIVKA-II performance in the diagnosing HCC as an individual biomarker was remarkable. The combined detection of PIVKA-II and AFP improved the diagnostic efficiency of HCC. PIVKA-II retained significant diagnosis capabilities for AFP-negative HCC patients. Significant correlations were found between PIVKA-II expression levels and some clinicopathological characteristics, including tumor size, tumor stage, tumor metastasis, differentiation degree and complications. PIVKA-II expression obviously decreased after surgical resection.ConclusionsPIVKA-II is a promising serum biomarker for the HCC diagnosis that can be used as a supplement for AFP. The combined diagnosis of the two markers greatly improved the diagnostic efficiency of HCC. The PIVKA-II levels in HCC patients were widely associated with clinicopathological characteristics representing tumor cell dissemination and/or poor prognosis. PIVKA-II can be used to evaluate the curative effects of HCC resection.

HCC poses a significant global health burden, with HBV being the predominant etiology in China. However, current diagnostic markers lack the requisite sensitivity and specificity. This study aims to develop and validate serum N-glycomics-based models for the diagnosis and prognosis of HCC in patients with chronic hepatitis B-related cirrhosis. This study enrolled a total of 397 patients with chronic hepatitis B-related cirrhosis and HCC for clinical management. N-glycomics profiling was conducted on all participants, and clinical data were collected. First, machine learning-based models, Hepatocellular Carcinoma Glycomics Random Forest model and Hepatocellular Carcinoma Glycomics Support Vector Machine model, were established for early screening and diagnosis of HCC using N-glycomics. The AUC values in the validation set were 0.967 (95% CI: 0.930-1.000) and 0.908 (0.840-0.976) for Hepatocellular Carcinoma Glycomics Random Forest model and Hepatocellular Carcinoma Glycomics Support Vector Machine model, respectively, outperforming AFP (0.687 [0.575-0.765]) and Protein Induced by Vitamin K Absence or Antagonist-II (PIVKA-II) (0.665 [0.507-0.823]). It also showed superiority in subgroup analysis and external validation. Calibration and decision curve analysis also showed good predictive performance. Additionally, we developed a prognostic model, the prog-G model, based on N-glycans to monitor recurrence in patients with HCC after curative treatment. During the follow-up period, it was observed that this model correlated with the clinical condition of the patients and could identify all recurrent HCC cases (n=12) prior to imaging findings, outperforming AFP (n=7) and PIVKA-II (n=9), while also detecting recurrent lesions earlier than imaging. N-glycomics models can effectively predict the occurrence and recurrence of HCC to improving the efficiency of clinical decision-making and promoting the precision treatment of HCC.

BackgroundHepatocellular carcinoma (HCC) is the most common malignant tumor of the liver, and its morbidity and mortality have been increasing in recent years. The early diagnosis and prompt treatment of small HCC are crucial to improve the prognosis and quality of life of patients. In China, hepatitis B virus infection is the main cause. HCC with a single tumor nodule of ≤ 3 cm in diameter, or HCC with a number of nodules, in which each nodule is ≤ 2 cm in diameter, with a total diameter of ≤ 3 cm, is considered as small HCC. The MRI liver-specific contrast agent can detect small HCC at the early stage. This has important clinical implications for improving the survival rate of patients.Main bodyGd-EOB-DTPA-enhanced MRI can significantly improve the sensitivity and specificity of the detection of HBV-related small hepatocellular carcinoma, providing an important basis for the clinical selection of appropriate personalized treatment. Gd-EOB-DTPA-enhanced MRI can reflect the degree of HCC differentiation, and the evaluation of HCC on Gd-EOB-DTPA-enhanced MRI would be helpful for the selection of the treatment and prognosis of HCC patients. The present study reviews the progress of the application of Gd-EOB-DTPA in the early diagnosis of small HCC, its clinical treatment, the prediction of the degree of differentiation, and the assessment of recurrence and prognosis of HCC, including the pharmacoeconomics and application limitations of Gd-EOB-DTPA. The value of the application of HCC with the Gd-EOB-DTPA was summarized to provide information for improving the quality of life and prolonging the survival of patients.ConclusionGd-EOB-DTPA-enhanced MRI has the diagnostic capability for small HCC with a diameter of ≤ 2 cm. This will have a broader application prospect in the early diagnosis of small liver cancer with a diameter of ≤ 1 cm in the future. The relationship between GD-EOB-DTPA-MRI and the degree of HCC differentiation has a large research space, and Gd-EOB-DTPA is expected to become a potential tool for the preoperative prediction and postoperative evaluation of HCC, which would be beneficial for more appropriate treatments for HCC patients.

Purpose: This study aims to develop liquid biopsy assays for early HCC diagnosis and prognosis. Methods: Twenty-three microRNAs were first consolidated as a panel (HCCseek-23 panel) based on their reported functions in HCC development. Serum samples were collected from 103 early-stage HCC patients before and after hepatectomy. Quantitative PCR and machine learning random forest models were applied to develop diagnostic and prognostic models. Results: For HCC diagnosis, HCCseek-23 panel demonstrated 81% sensitivity and 83% specificity for identifying HCC in the early-stage; it showed 93% sensitivity for identifying alpha-fetoprotein (AFP)-negative HCC. For HCC prognosis, the differential expressions of 8 microRNAs (HCCseek-8 panel: miR-145, miR-148a, miR-150, miR-221, miR-223, miR-23a, miR-374a, and miR-424) were significantly associated with disease-free survival (DFS) (Log-rank test p-value = 0.001). Further model improvement using these HCCseek-8 panel in combination with serum biomarkers (i.e. AFP, ALT, and AST) demonstrated a significant association with DFS (Log-rank p-value = 0.011 and Cox proportional hazards analyses p-value = 0.002). Conclusion: To the best of our knowledge, this is the first report to integrate circulating miRNAs, AST, ALT, AFP, and machine learning for predicting DFS in early HCC patients undergoing hepatectomy. In this setting, HCCSeek-23 panel is a promising circulating microRNA assay for diagnosis, while HCCSeek-8 panel is promising for prognosis to identify early HCC recurrence.

BackgroundHepatocellular carcinoma (HCC) is one of the most prevalent types of cancer and is responsible for close to one million annual deaths globally. In Pakistan, HCC accounts for 10.7% of cancer incidence. Prior studies indicated an association between interleukin 4 (IL-4) and cytotoxic T lymphocyte protein 4 (CTLA-4) gene polymorphisms in many types of cancers, including HCC that are either hepatitis B virus (HBV)- or hepatitis C Virus (HCV)-induced. The association of IL-4 and CTLA-4 genetic polymorphisms with HCV-induced HCC is not yet determined in the Pakistani population. Therefore, this research is designed to investigate the implication of IL-4 and CTLA-4 gene polymorphisms by determining the association of IL-4 -590 C/T (rs2243250) and CTLA-4 + 49 A/G (rs231775) with HCC in Pakistan.MethodsDifferent bioinformatics tools were employed to determine the pathogenicity of these polymorphisms. Samples were collected from HCV-induced HCC patients, followed by DNA extraction and ARMS-PCR analysis.ResultsThe SNP analysis results indicated a positive association of IL-4 -590C/T and CTLA-4 + 49A/G gene polymorphisms with HCV-induced HCC in Pakistan. The CTLA-4 polymorphism might enhance therapeutic efficiency of HCC chemotherapy medicines. The IL-4 polymorphism might introduce new transcription factor binding site in IL-4 promoter region.ConclusionThis study delineated risk factor alleles in CTLA-4 and IL-4 genes associated with HCV-mediated HCC among Pakistani patients that may have application to serve as genetic markers for pre- and early diagnosis and prognosis of HCC in HCV patients.

BackgroundHepatocellular carcinoma (HCC) is one of the most prevalent malignancies with poor prognosis. There is no research about the clinical significance of serum soluble CD155 (sCD155) level for HCC. We aim to explore the prognostic and diagnostic value of sCD155 in HCC patients undergoing curative resection.MethodsSerum sCD155 level in HCC patients was determined by enzyme‐linked immunosorbent assay. The prognostic significance of sCD155 was evaluated by Cox regression and Kaplan–Meier analyses. CD155 expression and biomarkers of immune cells in HCC tissues were detected by immunohistochemistry staining. The diagnostic significance of sCD155 was evaluated using receiver operating characteristic curve.ResultsSerum sCD155 level was significantly increased in HCC patients and predicted poor prognosis. The prognostic value of sCD155 remained in low recurrent risk subgroups of HCC. Serum sCD155 level was positively related to CD155 expression in HCC tissues. High serum sCD155 level was associated with decreased numbers of CD8+T cells and CD56+NK cells and increased number of CD163+M2 macrophages. Serum sCD155 level had better performance in distinguishing HCC patients from healthy donors and patients with chronic liver conditions than α‐fetoprotein. Among patients with α‐fetoprotein ≤ 20 ng/ml, serum sCD155 level could differentiate HCC patients from non‐HCC patients.ConclusionSerum sCD155 level represents a promising biomarker for diagnosis and prognosis of HCC. High serum sCD155 level may reflect an immunosuppressive tumor microenvironment in HCC.

Overview: Hepatocellular carcinoma is a complex disease and has a high mortality rate. Identifying biomarkers that can use to diagnose early and prognosis of HCC is essential to reduce the burden of HCC on patients, families, and society. Methods: The bioinformatics methods were used to study the expression of the SET nuclear proto-oncogene gene in cells, tissues, and the correlation of SET with hepatocellular carcinoma. The data from the open databases were used in this study include COMPARTMENTS, Kaplan-Meier Plotter, STRING, TIMER, UALCAN, The Cancer Genome Atlas database, and Gene Expression Omnibus. Results: At the cellular level, the expression level of the SET gene was highest in the nucleus, endoplasmic reticulum, cytosol. The SET gene's mRNA expression appeared in all body tissues. The TPM median of the SET gene in liver tissue was 33.42. The expression level of SET in hepatocellular carcinoma tissue was higher than that in non-cancer tissue for both males and females. The SET gene is an independent factor for the diagnosis and prognosis of HCC. Patients with high SET expression have a short survival time and a higher rate of recurrence than patients with low SET expression. The SET expression has a significant correlation with B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and especially dendritic cells in hepatocellular carcinoma. Conclusion: High expression level of SET related to a poor prognosis in patients with hepatocellular carcinoma. This study demonstrates that the SET is a potential biomarker for early diagnosis and prognosis of hepatocellular carcinoma.

BackgroundHepatocellular carcinoma (HCC) is one of the most common type of cancers, but there is still a lack of known biomarkers for the effective diagnosis or prognosis of HCC. Myristoylated alanine-rich C-kinase substrate (MARCKS) is a substrate of protein kinase C, which was located in the cell plasma membrane. The purpose of our study was to evaluate the role of MARCKS in HCC.MethodsThe role of MARCKS in HCC was explored by bioinformatics and experiment.ResultsWe demonstrated that MARCKS expression was significantly elevated in HCC datasets of TCGA. MARCKS was up-regulated in tumor sample in HCC. Functional enrichment indicated that MARCKS-related differentially expressed genes (DEGs) were mainly enriched in cell junction tissue, response to growth factors and cell population proliferation. Tumor and ECM-receptor interactions related pathways were enriched by the KEGG. MARCKS expression in HCC patients was higher in females, younger individuals, and those at worse clinical stages. Cox regression analysis showed that MARCKS expression was a risk factor for overall survival and disease-specific survival of patients.ConclusionMARCKS was up-regulated in HCC, may play a crucial role in HCCs, and has prognostic value for clinical outcomes.