Diagnostic Marker For Hepatocellular Carcinoma Research Articles

Circulating miRNA’s biomarkers for early detection of hepatocellular carcinoma in Egyptian patients based on machine learning algorithms

Liver cancer, which ranks sixth globally and third in cancer-related deaths, is caused by chronic liver disorders and a variety of risk factors. Despite therapeutic improvements, the prognosis for Hepatocellular Carcinoma (HCC) remains poor, with a 5-year survival rate for advanced cases of less than 12%. Although there is a noticeable decrease in the frequency of cases, liver cancer remains a significant worldwide health concern, with estimates surpassing one million cases by 2025. The prevalence of HCC has increased in Egypt, and it includes several neoplasms with distinctive messenger RNA (mRNA) and microRNA (miRNA) expression profiles. In HCC patients, certain miRNAs, such as miRNA-483-5P and miRNA-21, are upregulated, whereas miRNA-155 is elevated in HCV-infected people, encouraging hepatocyte proliferation. Short noncoding RNAs called miRNAs in circulation have the potential as HCC diagnostic and prognostic markers. This paper proposed a model for examining circulating miRNAs as diagnostic and predictive markers for HCC in Egyptian patients and their clinical and pathological characteristics. The proposed HCC detection model consists of three main phases: data preprocessing phase, feature selection based on the proposed Binary African Vulture Optimization Algorithm (BAVO) phase, and finally, classification as well as cross-validation phase. The first phase namely the data preprocessing phase tackle the main problems associated with the adopted datasets. In the feature selection based on the proposed BAVO algorithm phase, a new binary version of the BAVO swarm-based algorithm is introduced to select the relevant markers for HCC. Finally, in the last phase, namely the classification and cross-validation phase, the support vector machine and k-folds cross-validation method are utilized. The proposed model is evaluated on three studies on Egyptians who had HCC. A comparison between the proposed model and traditional statistical studies is reported to demonstrate the superiority of using the machine learning model for evaluating circulating miRNAs as diagnostic markers of HCC. The specificity and sensitivity for differentiation of HCC cases in comparison with the statistical-based method for the first study were 98% against 88% and 99% versus 92%, respectively. The second study revealed the sensitivity and specificity were 97.78% against 90% and 98.89% versus 92.5%, respectively. The third study reported 83.2% against 88.8% and 95.80% versus 92.4%, respectively. Additionally, the results show that circulating miRNA-483-5p, 21, and 155 may be potential new prognostic and early diagnostic biomarkers for HCC.

Red Blood Cell Distribution Width as a Diagnostic Marker of Hepatocellular Carcinoma in Cirrhotic Patients

Background and Aim Although α-fetoprotein (AFP) is the main marker used for the diagnosis of hepatocellular carcinoma(HCC), its sensitivity and specificity as a screening tool have been questionable. Red blood cell distribution width (RDW) has been involved as a prognostic tool for many diseases and cancers including liver diseases. Still, its role in the diagnosis of HCC needs to be identified. This study aimed to evaluate the clinical importance of RDW as a novel marker in the diagnosis of HCC in Egyptian cirrhotic patients. Patients and Methods This cross-sectional study was carried out on 162 cirrhotic patients who attended Tropical medicine department clinics and inpatient wards at the Faculty of Medicine, Tanta University. Then they were divided into 2 groups of 81 patients each depending on their diagnosis with or without HCC (group I and group II respectively). Complete blood picture (CBC) that included red cell distribution width- coefficient of variation (RDW-CV) and AFP were obtained from all patients. Results There was a statistically significant elevation in RDW-CV in the HCC group as its mean± SD was 15.2.± 1.86 in HCC group versus 13.8 ± 1.99 in non HCC group (P<0.001). In addition, AFP was significantly elevated in group I than in group II (P<0.001). RDW-CV at a cut–off >14% had a 66.76%sensitivity and 61.73%specificity while AFP at a cut-off value>20 ng/ml had a 60.49%sensitivity and 79.01%specificity in the diagnosis of HCC. The combination of RDW-CV and AFP increased the sensitivity and specificity for the diagnosis of HCC(72.84% and 87.65% respectively) than each marker alone. Conclusions RDW may be considered a novel and cheap biomarker for the diagnosis of HCC either alone or in combination with AFP as it is readily available in CBC and does not need sophisticated techniques.

MiR-203 and Endocan as Diagnostic Markers for Hepatocellular Carcinoma Related Viral Infections

MiR-203 and Endocan as Diagnostic Markers for Hepatocellular Carcinoma Related Viral Infections

Systematic review: Glycomics as diagnostic markers for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer with one of the highest cancer-related mortality rates worldwide. Early diagnosis is crucial for improving the therapeutic options and reducing the disease-related mortality. To investigate serum N-glycomics as diagnostic markers for HCC. We performed a comprehensive search in PubMed, EMBASE, Web of Science and Scopus through August 17, 2023. Eligible studies assessed the potential use of serum N-glycomics as diagnostic biomarkers for HCC. Study selection, data extraction and quality assessment were performed by two independent reviewers. Of the 48 articles included, 11 evaluated the utility of N-glycomics for the diagnosis of HCC in whole serum while the remaining articles focused on specific protein glycoforms or protein levels. Of these specific proteins, haptoglobin, alpha-fetoprotein (AFP), kininogen (Kin), α-1-antitrypsin and Golgi protein 73 (GP73) were the most frequently studied. Increased levels of fucosylation and branching presented as the most prevalent post-translational modifications of glycoproteins in patients with HCC compared to controls. Notably, glycomics-based biomarkers may provide a clinical benefit for the diagnosis of early HCC, as several algorithms achieved AUCs between 0.92-0.97. However, these were based on single studies with limited sample sizes and should therefore be validated. Alterations in serum N-glycomics, characterised by increased levels of fucosylation and branching, have potential as diagnostic biomarkers for HCC. Optimisation of study design, patient selection and analysing techniques are needed before clinical implementation will be possible.

Hepatocellular carcinoma cell-derived small extracellular vesicle-associated CD147 serves as a diagnostic marker and promotes endothelial cell angiogenesis via the PI3K/Akt pathway

Aim: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. The process of HCC development is closely related to angiogenesis. Plasma exosomes have diagnostic value in many diseases and have become a current research hotspot. We aimed to identify a key molecule in small extracellular vesicles (sEVs) involved in angiogenesis as a diagnostic marker for HCC and uncover the mechanism underlying its regulation in the angiogenesis process. Methods: Nano‐flow cytometer (nFCM) was used to detect CD147 expression in plasma-derived sEVs in 155 HCC patients, 59 liver cirrhosis (LC), and 82 healthy donors (HD). The mechanism of hepatocellular carcinoma cell-derived sEVs CD147 promoting angiogenesis was elucidated by cell proliferation assay, scratch wound healing assay, transwell assay, tube formation assay, and in vivo Matrigel plug angiogenesis assay. Results: We found that CD147 expression was significantly higher in HCC tissue samples than in normal tissues. We also found a significantly larger number of CD147-positive small extracellular vesicles (CD147+ sEVs) in the plasma of HCC patients than LC patients and HD. Furthermore, we showed that hepatocellular carcinoma cell (HepG2)-derived CD147+ sEVs promoted cell proliferation, migration, invasion, and angiogenesis in human umbilical vein endothelial cells. The CD147+ sEVs upregulated vascular endothelial growth factor A (VEGFA) by activating the PI3K/Akt pathway, thereby promoting angiogenesis. Conclusion: HCC-derived sEVs-associated CD147 serves as a diagnostic marker and promotes endothelial cell angiogenesis via the PI3K/Akt pathway.

The Gut Microbiome as a Biomarker and Therapeutic Target in Hepatocellular Carcinoma.

The microbiome is pivotal in maintaining health and influencing disease by modulating essential inflammatory and immune responses. Hepatocellular carcinoma (HCC), ranking as the third most common cause of cancer-related fatalities globally, is influenced by the gut microbiome through bidirectional interactions between the gut and liver, as evidenced in both mouse models and human studies. Consequently, biomarkers based on gut microbiota represent promising non-invasive tools for the early detection of HCC. There is a growing body of evidence suggesting that the composition of the gut microbiota may play a role in the efficacy of immunotherapy in different types of cancer; thus, it could be used as a predictive biomarker. In this review, we will dissect the gut microbiome's role as a potential predictive and diagnostic marker in HCC and evaluate the latest progress in leveraging the gut microbiome as a novel therapeutic avenue for HCC patients, with a special emphasis on immunotherapy.

Study for the Significance of Osteopontin vs Alpha Feto Protein as a Diagnostic Marker for Hepatocellular Carcinoma in Cirrhotic Patients with HCV

Abstract Background Outcome of hepatocellular carcinoma (HCC) depends mainly on its early diagnosis. The performance of traditional biomarkers is not satisfactory. Alpha-fetoprotein (AFP) is the most widely used serum biomarker for hepatocellular carcinoma (HCC), despite its limitations. Several studies have reported that osteopontin (OPN) is a promising marker for the diagnosis of hepatocellular carcinoma (HCC); however, some studies emerged with conflicting results, Aim of the Work To evaluate the clinical significance of the plasma osteopontin (OPN) versus alpha-fetoprotein (AFP) in the diagnosis of HCC in cirrhotic patients Patients and Methods This study was Case-Control study, was conducted at internal Medicine and Gastroenterology outpatient clinics and ward in Ain Shams University Hospitals on Patients divided into 3 groups: (Group 1): 50 patients with previously diagnosed HCC on top of chronic HCV induced cirrhosis, (Group II): 15 chronic HCV patients with cirrhosis, (Group III):15 healthy controls during a period of Six months Results There was high statistically significant difference between the studied groups as regard OPN and AFP, Conclusion Plasma OPN level was elevated in the HCV-related HCC patients by comparison to the chronic HCV patients with cirrhosis and healthy controls. OPN is a promising tumor marker that could be added to the current standard tests for the diagnosis of HCC in patients with liver cirrhosis, due to Chronic HCV infection, in order to detect the disease at an early stage and, hence, improve the prognosis and survival rates of these patients

Pan-Cancer Profiling and Digital Pathology Analysis Reveal Negative Prognostic Biomarker ZPR1 Associated with Immune Infiltration and Treatment Response in Hepatocellular Carcinoma.

ZPR1 is a zinc finger-containing protein that plays a crucial role in neurodegenerative diseases, lipid metabolism disorders, and non-alcoholic fatty liver disease. However, the expression pattern, prognostic value, and treatment response of ZPR1 in pan-cancer and hepatocellular carcinoma (HCC) remain unclear. Pan-cancer expression profiles and relevant clinical data were acquired from UCSC Xena platform. Pan-cancer expression, epigenetic profile, and clinical correlation analysis for ZPR1 were performed. We next explored the prognostic significance and potential biological functions of ZPR1 in HCC. Furthermore, the relationship between ZPR1 and immune infiltration and treatment response was investigated. Finally, quantitative immunohistochemistry (IHC) analysis was applied to assess the correlation of ZPR1 expression and immune microenvironment in HCC tissues using Qupath software. ZPR1 was differentially expressed in most tumor types and significantly up-regulated in HCC. ZPR1 showed hypo-methylated status in most tumors. Pan-cancer correlation analysis indicated that ZPR1 was closely associated with clinicopathological factors and TMB, MSI, and stemness index in HCC. High ZPR1 expression could be an independent risk factor for adverse prognosis in HCC. ZPR1 correlated with immune cell infiltration and therapeutic response. Finally, IHC results suggested that ZPR1 correlated with CD4, CD56, CD68, and PD-L1 expression and is a promising pathological diagnostic marker in HCC. Immune infiltrate-associated ZPR1 could be considered a novel negative prognostic biomarker for therapeutic response in HCC.

An electrochemiluminescence resonance energy transfer biosensor based on Luminol-LDH and CuS@Pt for detection of alpha-fetoprotein

Alpha-fetoprotein (AFP) is the best diagnostic marker for hepatocellular carcinoma (HCC) and plays an important role in the general surveillance of the population. Therefore, the establishment of an ultra-sensitive AFP assay is essential for the early screening and clinical diagnosis of HCC. In this work, we designed a signal-off biosensor for ultra-sensitive detection of AFP based on an electrochemiluminescent resonance energy transfer (ECL-RET) strategy using luminol intercalated layered bimetallic hydroxide (Luminol-LDH) as an ECL donor and Pt nanoparticles-grown on copper sulfide nanospheres (CuS@Pt) as ECL acceptor. The (Au NPs/Luminol-LDH)n multilayer nanomembrane synthesized by our intercalation and layer-by-layer electrostatic assembly process not only effectively immobilizes luminol but also significantly enhances the ECL signal. The CuS@Pt composite has well visible light absorption ability and can burst the light emitted from luminol by ECL-RET. The biosensor showed good linearity in the range from 10−5 ng mL−1 to 100 ng mL−1 and a minimum detection limit of 2.6 fg mL−1. Therefore, the biosensor provides a novel and efficient strategy for the detection of AFP, which is important for the early screening and clinical diagnosis of HCC.

Heat shock proteins as diagnostic markers for hepatocellular carcinoma: a novel approach

Hepatocellular carcinoma (HCC) is a malignant tumor of the liver. Heat shock proteins play their part in response to cellular stress. They are overexpressed in many forms of cancers where they shield malignant cells from stressful environment thus contributing to poor prognosis and treatment resistance. HSP 27, a heat shock protein mostly associated with Hepatitis induced hepatocellular cancer, inhibits apoptosis and HSP 70 along with HSP 90 contributes to tumor metastasis. HSP 70 count is higher in tumor cells in comparison with normal cells and it is related to tumor size, stage and vessel invasion while HSP 20 count regresses as tumor progresses. Considering all these factors, differentiation of HCC from other liver pathologies becomes much easier at an early stage. Early diagnosis of HCC is important and timely and prompt treatment can decrease the mortality associated with HCC. On the grounds of many useful characteristics like early detection and accuracy in detailing of size, invasion and metastasis of tumor our Review suggests that along with it all HSPs also have therapeutic potential as targeting the specific markers can help patients diagnosed with HCC. HSPs are the innovation from diagnosis to management to cure of HCC. Extensive research exploring Heat Shock Proteins and Hepatocellular Carcinoma was done on search engines such as Science Direct, OVID, Google Scholar, PubMed, and MEDLINE. Articles published in languages other than English were also considered. Data that were solely published in conference or meeting proceedings, websites, or books were not included.

Assessment of serum CXCL9 and pentraxin 3 as novel markers for hepatocellular carcinoma in cirrhotic hepatitis C patients.

Hepatocellular carcinoma (HCC) is the most frequent primary cancer of the liver. It is also one of the world's most common cancers and an important leading cause of cancer mortality in many parts of the world. As a result, it is essential to look for efficient markers for early and accurate HCC diagnosis. CXCL9 and pentraxin 3 are involved in the pathway of many cancers. The aim of the study was to assess the value of serum CXCL9 and pentraxin 3 as diagnostic markers of HCC among cirrhotic hepatitis C virus (HCV) patients. The current study was conducted on 90 candidates divided into 3 groups: group I - 30 patients with HCV induced liver cirrhosis without HCC; group II - 30 patients with HCV induced liver cirrhosis with HCC; group III - 30 healthy subjects (control group). All candidates were subjected to detailed history taking and thorough clinical examination, laboratory investigations, serum CXCL9, serum pentraxin 3, ultrasound abdomen and CT triphasic liver in group III. Serum CXCL9 and serum pentraxin 3 levels were significantly higher in group II than group I and significantly higher in group I than group III. Serum CXCL9 and serum pentraxin 3 could be utilized as diagnostic markers for HCC.

Clinical value of serum AFP and PIVKA‐II for diagnosis, treatment and prognosis of hepatocellular carcinoma

The accuracy of alpha-fetoprotein (AFP) as a diagnostic marker for hepatocellular carcinoma (HCC) is insufficient, and the application of abnormal prothrombin (PIVKA-II) in HCC is still controversial. Serum AFP and PIVKA-II levels were analyzed in 145 cases of HCC, 57 of benign liver disease, 55 of cholangiocarcinoma and gallbladder carcinoma, 112 of other gastrointestinal tumors with liver metastasis, and 101 healthy controls. Receiver operating characteristic curve and area under the curve were used to evaluate the diagnostic value of AFP and PIVKA-II for HCC. The changes in serum AFP and PIVKA-II levels before and after treatment in 47 HCC patients who underwent surgery and 77 who received interventional treatment were used to evaluate treatment efficacy and prognosis in HCC. The concentrations of AFP and PIVKA-II in the HCC group were significantly higher than those in other groups (p < 0.01). The diagnostic value of PIVKA-II in HCC was better than that of AFP, and combined detection improved the diagnostic sensitivity and specificity. The levels of AFP and PIVKA-II after liver cancer surgery were significantly lower than those before surgery. Elevated levels of PIVKA-II before surgery predicted disease progression, and patients who remained positive for PIVKA-II after surgery had worse prognosis than those who became negative after surgery. Combined detection of AFP and PIVKA-II is superior to both tests alone. We found that higher serum level of PIVKA-II indicates more severe HCC, with worse prognosis, while the level of AFP had no correlation with the prognosis.

Circulating MicroRNA Panel as a Diagnostic Marker for Hepatocellular Carcinoma.

Current diagnostic markers for hepatocellular carcinoma are compromised and limited by their low sensitivity and speci- ficity. In this study, circulating microRNAs were utilized as a diagnostic tool to segregate hepatocellular carcinoma patients from healthy subjects. We analyzed 2 public datasets for differences in plasma microRNA expression profiles of hepatocellular carcinoma patients and healthy controls to identify biomarkers related to hepatocellular carcinoma. Plasma samples from hepatocellular carcinoma patients and control subjects were then collected for next-generation microRNA sequencing analysis. The differential microRNAs obtained from the above 3 parts were intersected to obtain microRNAs that were significantly different between the 2 groups. We then analyzed 58 specimens, which come from hepatocellular carcinoma and the control group, for validation through a quantitative polymerase chain reaction. The diagnostic value of these differentially expressed miRNAs was assessed by receiver operating characteristic curve analysis. The levels of miR-206 and miR-222 were significantly higher (P &lt; .05) and the level of miR-126 was lower (P &lt; .05) in patients with hepatocellular carcinoma than in healthy subjects. Receiver operating characteristic analysis established a powerful diagnostic accuracy when miR-206, miR-222, and miR-126 were combined (area under curve = 0.887), which was similar to that of the markerα-fetoprotein (area under curve = 0.889). When the microRNAs were combined with α-fetoprotein, the accuracy of hepatocellular carci- noma diagnostic potential was further improved (area under curve = 0.989). We identified 3 microRNAs significantly altered in the plasma of hepatocellular carcinoma patients and they can screen patients at risk of hepatocellular carcinoma.

RPNs Levels Are Prognostic and Diagnostic Markers for Hepatocellular Carcinoma.

The ribophorin family (RPN) is an essential regulatory subunit of the proteasome. By influencing the ubiquitin-proteasome system activity, ribophorins (RPNs) are responsible for almost all physiology and pathology processes of mammalian cells. Nevertheless, little is known about the role of RPNs in HCC. In this work, we first evaluated the transcriptional levels and the prognostic and diagnostic value of RPNs based on the public database. Firstly, we found all RPNs were surprisingly consistently upregulated in HCC tissues. Moreover, the RPNs' expression pattern is correlated with HCC tumor grade. The TCGA HCC platforms' data indicated that RPN2, RPN3, RPN6, RPN9, RPN10, RPN11, and RPN12 have robust diagnosis values. Then, survival analysis revealed that the high expression of RPN1, RPN2, RPN4, RPN5, RPN6, RPN9, and RPN11 was correlated with unfavourable HCC overall survival. Then, genetic alteration, immune infiltration feature, gene-genes network, and functional enrichment for RPNs indicated that RPNs have many potential biosynthesis activities expert for UPS functions. Moreover, western blot and qRT-PCR results confirmed these results. The silencing of RPN6 and RPN9 significantly reduced HCC cells' proliferation, migration, and invasion ability in vitro. An in vivo tumor model further validated the oncogene effect of RPN6 on HCC cell growth. Moreover, RPN6 and RPN9 could promote cell migratory and invasive potential by affecting the epithelial-mesenchymal transition (EMT) process. In summary, this study suggests that the RPN family has the potential to be potential biomarkers and targets for HCC.

A Novel circRNA hsa_circRNA_002178 as a Diagnostic Marker in Hepatocellular Carcinoma Enhances Cell Proliferation, Invasion, and Tumor Growth by Stabilizing SRSF1 Expression.

Background Previous research studies have shown that the elevation of circular RNA (circRNA), hsa_circRNA_002178, was associated with the poor prognosis of breast cancer and colorectal cancer, while its molecular mechanisms underlying the effects on hepatocellular carcinoma (HCC) are still elusive. Methods The microarray dataset GSE97332 was obtained from the Gene Expression Omnibus (GEO) database and calculated by using the GEO2R tool to identify differentially expressed circRNAs. Differentially expressed hsa_circRNA_002178, in 7 HCC tissue samples and paracancerous tissues, as well as in HCC cell lines and normal hepatocytes, was checked by RT-qPCR. Cell proliferation, invasion, migration, and epithelial-to-mesenchymal transition (EMT)-related proteins were tested in hsa_circRNA_002178-overexpressed or hsa_circRNA_002178-knocked down HCC cells. Subsequently, we identified whether hsa_circRNA_002178 binds to serine- and arginine-rich splicing factor 1 (SRSF1) and then analyzed their function in regulating HCC cell behavior. The effect on HCC cell xenograft tumor growth was observed by the knockdown of hsa_circRNA_002178 in vivo. Results GEO2R-based analysis displayed that hsa_circRNA_002178 was upregulated in HCC tissues. Overexpression or knockdown of hsa_circRNA_002178 encouraged or impeded HCC cell proliferation, migration, invasion, and EMT program. Mechanically, hsa_circRNA_002178 bound to SRSF1 3′-untranslated region (UTR) and stabilized its expression. SRSF1 weakening eliminated the effects of pcDNA-hsa_circRNA_002178 on cell malignant behavior. Finally, the knockdown of hsa_circRNA_002178 was confirmed to prevent xenograft tumor growth. Conclusions hsa_circRNA_002178 overexpression encouraged the stability of SRSF1 mRNA expression, and it may serve as an upstream factor of SRSF1 for the diagnosis of HCC.

Integrated Analysis of Tumor Mutation Burden and Immune Infiltrates in Hepatocellular Carcinoma.

Tumor mutation burdens (TMBs) act as an indicator of immunotherapeutic responsiveness in various tumors. However, the relationship between TMBs and immune cell infiltrates in hepatocellular carcinoma (HCC) is still obscure. The present study aimed to explore the potential diagnostic markers of TMBs for HCC and analyze the role of immune cell infiltration in this pathology. We used OA datasets from The Cancer Genome Atlas database. First, the “maftools” package was used to screen the highest mutation frequency in all samples. R software was used to identify differentially expressed genes (DEGs) according to mutation frequency and perform functional correlation analysis. Then, the gene ontology (GO) enrichment analysis was performed with “clusterProfiler”, “enrichplot”, and “ggplot2” packages. Finally, the correlations between diagnostic markers and infiltrating immune cells were analyzed, and CIBERSORT was used to evaluate the infiltration of immune cells in HCC tissues. As a result, we identified a total of 359 DEGs in this study. These DEGs may affect HCC prognosis by regulating fatty acid metabolism, hypoxia, and the P53 pathway. The top 15 genes were selected as the hub genes through PPI network analysis. SRSF1, SNRPA1, and SRSF3 showed strong similarities in biological effects, NCBP2 was demonstrated as a diagnostic marker of HCC, and high NCBP2 expression was significantly correlated with poor over survival (OS) in HCC. In addition, NCBP2 expression was correlated with the infiltration of B cells (r = 0.364, p = 3.30 × 10−12), CD8+ T cells (r = 0.295, p = 2.71 × 10−8), CD4+ T cells, (r = 0.484, p = 1.37 × 10−21), macrophages (r = 0.551, p = 1.97 × 10−28), neutrophils (r = 0.457, p = 3.26 × 10−19), and dendritic cells (r = 0.453, p = 1.97 × 10−18). Immune cell infiltration analysis revealed that the degree of central memory T-cell (Tcm) infiltration may be correlated with the HCC process. In conclusion, NCBP2 can be used as diagnostic markers of HCC, and immune cell infiltration plays an important role in the occurrence and progression of HCC.

Serum exosomal miRNA-720 as a diagnostic marker for hepatocellular carcinoma

Serum exosomal miRNA-720 as a diagnostic marker for hepatocellular carcinoma

Neuropilin1 as a diagnostic marker for Hepato-cellular Carcinoma

Neuropilin1 as a diagnostic marker for Hepato-cellular Carcinoma

Evaluation of plasma LC3B+extracellular vesicles as a potential novel diagnostic marker for hepatocellular carcinoma

BackgroundCirculating extracellular vesicles (EVs) are recognized as a promising source of cancer biomarkers. We previously reported that tumor cell-released autophagosomes, a new subgroup of EVs expressing the mature autophagosome-specific marker LC3B (LC3B+ EVs), are critical modulators of host anti-tumor immunity. This study aimed to assess the level of plasma LC3B+ EVs and the correlation with clinical outcomes in liver cancer patients. MethodsThe plasma and ascites samples were obtained from patients with liver cancer, non-malignant liver disease, and healthy controls. EVs were isolated by differential centrifugation and characterized using flow cytometry, nanoparticle tracking analysis, transmission electron microscopy, and western blotting. Receiver operating characteristic curve (ROC) was used to evaluate the diagnostic efficacy of plasma LC3B+ EVs or HSP90α+LC3B+ EVs from liver cancer patients. The relationship between the expression levels of HSP90AA1 or MAP1LC3B and survival were analyzed using patient data from the TCGA database. The correlation between HSP90α in LC3B+ EVs and PD-1highCD8+ exhausted T cells from the ascites and peripheral blood of liver cancer patients was also evaluated. ResultsThe EVs preparation from liver cancer patients contained LC3B+ EVs expressing epithelial tumor cell adhesion molecules (EpCAM), indicating that these LC3B+ EVs originated from epithelial tumor cells. The levels of plasma LC3B+ EVs and HSP90α+LC3B+ EVs in liver cancer patients were significantly higher than in non-malignant liver disease patients and healthy controls. The expression of HSP90α in plasma LC3B+ EVs (AUC 0.9595, sensitivity 86.00%, specificity 96.67%) accurately differentiated liver cancer patients from non-liver cancer controls. Additionally, a significant decrease in the levels of plasma LC3B+ EVs and HSP90α+LC3B+ EVs was found post-surgery in each patient, and high expression of HSP90AA1 or MAP1LC3B in the tumor tissue correlated with significantly worse survival compared to those with low expression. We also observed that the level of LC3B+ EVs and HSP90α+LC3B+ EVs positively correlated with the PD-1highCD8+ exhausted T cells in liver cancer patients. Human CD8+ T cells treated with purified LC3B+ EVs in vitro exhibited a dose-dependent increase in the percentage of PD-1+CD8+ T cells, whereas the production of IFN-γ was decreased. ConclusionsWe demonstrated that isolation and detection of plasma LC3B+ EVs carrying bioactive molecules is an effective diagnostic marker of liver cancer, and may also be used as a potential marker for immune monitoring and predicting prognosis clinically.

Circ-CFH promotes the development of HCC by regulating cell proliferation, apoptosis, migration, invasion, and glycolysis through the miR-377-3p/RNF38 axis.

Circular RNAs (circRNAs) have previously been confirmed to function as vital regulators in multiple human cancers, including hepatocellular carcinoma (HCC). This study aimed to clarify the role and underlying molecular mechanisms of circ-CFH in HCC. circ-CFH was overexpressed in HCC tissues and cells, and the downregulation of circ-CFH inhibited the development of HCC by repressing cell proliferation, migration, invasion, and glycolysis while enhancing apoptosis in vitro, as well as inhibited tumor growth in vivo. miR-377-3p was negatively regulated by circ-CFH, and silencing of miR-377-3p abolished circ-CFH knockdown-mediated effects on HCC cells. Moreover, overexpression of miR-377-3p could impede the HCC process by targeting RNF38. Mechanistically, the circ-CFH/miR-377-3p/RNF38 axis regulated the progression of HCC cells, which might provide new diagnostic markers for HCC.