Biomarker For Hepatocellular Carcinoma Research Articles

Recent Advances in Liver Transplantation for Hepatocellular Carcinoma.

Liver transplantation for hepatocellular carcinoma (HCC) remains an evolving field. Major challenges HCC transplant patients face today include liver organ donor shortages and the need for both better pre-transplant bridging/downstaging therapies and post-transplant HCC recurrence treatment options. The advent of immunotherapy and the demonstrated efficacy of immune checkpoint inhibitors in multiple solid tumors including advanced/unresectable HCC hold promise in expanding both the neoadjuvant and adjuvant HCC transplant treatment regimen, though caution is needed with these immune modulating agents leading up to and following transplant. New options for pre-transplant HCC management will expand access to this curative option as well as ensure patients have adequate control of their HCC prior to transplant to maximize the utility of a liver donor. Machine perfusion has been an active area of investigation in recent years and could expand the organ donor pool, helping address current liver donor shortages. Finally, additional HCC biomarkers such as AFP-L3 and DCP have shown promise in improving risk stratification of HCC patients. Together, these three recent advancements will likely alter HCC transplant guidelines in the coming years.

Circulatory Agrin Serves as a Prognostic Indicator for Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC), the predominant form of liver cancer, is associated with high mortality rates both in the United States and globally. Despite current advances in immunotherapy regimens, there is a scarcity of biomarkers to guide therapy selection. Alpha-fetoprotein (AFP) and glypican-3 have been proposed as biomarkers for HCC, but they do not provide any prognostic benefit for modeling disease progression. Agrin, a secreted proteoglycan, is frequently overexpressed in HCC and plays prominent role(s) in the liver tumor microenvironment (TME) to promote hepatocarcinogenesis. Here we employed a pilot single-center retrospective investigation to assess the prognostic value of agrin in HCC. Our evidence suggests that elevated serum agrin levels are associated with poor prognosis and performance among HCC patients. Multivariate Cox regression models indicate that secreted agrin serves as a better prognostic indicator compared to AFP that is significantly correlated with other secreted biomarkers (e.g., IL6). Cumulatively, this work demonstrates a promising clinical value of agrin in the detection and prognosis of HCC.

Immune landscape of hepatocellular carcinoma: The central role of TP53-inducible glycolysis and apoptosis regulator.

This study aims to address the substantive issue of lacking reliable prognostic biomarkers in hepatocellular carcinoma (HCC) by investigating the relationship between TP53-inducible glycolysis and apoptosis regulator (TIGAR) and HCC prognosis using The Cancer Genome Atlas database. (1) Integrated statistical analyses, including logistic regression, Wilcoxon signed-rank test, and Kruskal-Wallis test, were conducted to explore the association between TIGAR expression and clinical-pathological features of HCC. (2) The Kaplan-Meier method combined with univariate and multivariate Cox regression models underscored TIGAR as a prognostic factor in HCC. (3) Gene set enrichment analysis (GSEA) revealed key pathways associated with TIGAR, while single-sample gene set enrichment analysis (ssGSEA) determined its relevance to cancer immune infiltration. (1) Elevated TIGAR expression was significantly correlated with decreased survival outcomes in HCC patients. (2) GSEA highlighted the significant link between TIGAR and humoral immunity. (3) ssGSEA revealed a positive correlation between TIGAR expression and infiltration of Th1 and Th2 cells and a negative correlation with Th17 cell infiltration. TIGAR, as a potential prognostic biomarker for HCC, holds significant value in immune infiltration. Understanding the role of TIGAR could contribute to improved prognostic predictions and personalized treatment strategies for HCC patients.

Prognostic significance of pyrimidine metabolism-related genes as risk biomarkers in hepatocellular carcinoma

Hepatocellular carcinoma (HCC), as a malignancy derived from liver tissue, is typically associated with poor prognosis. Increasing evidence suggests a connection between pyrimidine metabolism and HCC progression. The purpose of this study was to establish a model applied to the prediction of HCC patients’ overall survival. Transcriptomic data of HCC patients were downloaded from The Cancer Genome Atlas (TCGA) website. Pyrimidine metabolism-related genes (PMRGs) were collected from the Gene Set Enrichment Analysis (GSEA) website. Differential gene expression analysis was carried out on the HCC data, followed by an intersection of the differentially expressed genes (DEGs) and PMRGs. Subsequently, a prognostic model incorporating nine genes was established using univariate/multivariate Cox regression and Least absolute shrinkage and selection operator (LASSO) regression. Survival analysis demonstrated that the high-risk group defined by this model had considerably shorter overall survival than the low-risk group in both TCGA and Gene Expression Omnibus (GEO) datasets. Receiver operating characteristic (ROC) analysis indicated the good predictive capability of the model. CIBERSORT and single sample gene set enrichment analysis (ssGSEA) algorithms revealed significantly higher levels of Macrophages M0 and lower levels of natural killer (NK)_cells in the high-risk group compared to the low-risk group. The immunophenoscore (IPS) and the tumor immune dysfunction and exclusion (TIDE) score demonstrated that the model could significantly differentiate patients who would be more suitable for immunotherapy. Moreover, the CellMiner database was utilized to predict anti-tumor drugs significantly associated with the model genes. Collectively, the potential prognostic significance of pyrimidine metabolism in HCC was revealed in this study. The prognostic model aids in evaluating the survival time and immune status of HCC patients.

A candidate reference measurement procedure for quantification of glycocholic acid in human serum based on isotope dilution liquid chromatography-tandem mass spectrometry.

Accurate measurement of serum glycocholic acid (GCA) is crucial for evaluating the activity of chronic hepatitis. Moreover, GCA is a novel identified biomarker for hepatocellular carcinoma. Although some laboratories have used theliquid chromatography-tandem mass spectrometry (LC-MS/MS) method to measure GCA in recent years, the problem of potential interference of GCA analogues has not been solved well yet. Neither reference measurement procedures nor reference materials for GCA have been listed in the Joint Committee for Traceability in Laboratory Medicine (JCTLM) database. For standardization of GCA, it is urgent to establish a candidate measurement procedure for GCA. In this study, a candidate reference measurement procedure for the quantification of GCA in human serum based on isotope dilution liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) by a two-step sample pretreatment of protein precipitation and MAX solid-phase extraction was developed and validated. GCA can be completely separated from its structural analogues with gradient elution in 9 min compared with short time gradients published in previous literature by Huang's group. Method validation indicated perfect quantitation precision with intra-day and inter-day values that were ≤1.30% and ≤1.80%, respectively. The method showed excellent linearity with high regression coefficients (R2 > 0.999) over a range of 0.92 ng/g-38.38 μg/g and perfect recoveries at three spiked levels (99.87-100.43%). No interference, matrix effect, and carryover were observed. Moreover, the cRMP was successfully applied to measure GCA in serum samples and compared with two immunoassays in aclinical laboratory. As a candidate reference method, this method can promote aGCA standardization program.

Autophagy-related biomarkers in hepatocellular carcinoma and their relationship with immune infiltration

BackgroundAutophagy regulation plays vital roles in many cancers. We aimed to investigate the expression, prognostic value, and immune infiltration of autophagy-related genes in hepatocellular carcinoma (HCC) by bioinformatics analysis.MethodHuman autophagy-related differentially expressed genes (DEGs) between adjacent and HCC tissues were identified. We performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. We also evaluated immune infiltration and the response to tumor-sensitive drugs. Finally, we verified the expression of these proteins in clinical samples by immunohistochemistry (IHC), RNA isolation and real-time reverse transcription polymerase chain reaction (RT‒PCR).ResultsA total of 57 autophagy-related DEGs were identified. The HUB genes (BIRC5, CDKN2A, SPP1, and IGF1) were related to the diagnosis and prognosis of HCC. The HUB genes were significantly enriched in immune-related pathways. Furthermore, correlation analysis revealed that HUB gene expression was associated with immune infiltration. We identified 35 tumor-sensitive drugs targeting the HUB genes. Finally, by IHC, we discovered that the protein of CDKN2A, BIRC5, and SPP1 were upregulated in HCC tissues, while IGF1 was downregulated in HCC tissues compared with the levels in paracarcinoma tissues; by RT‒PCR, we discovered that the mRNA of CDKN2A, BIRC5, and SPP1 were upregulated in HCC tissues, while the mRNA of IGF1 was downregulated in HCC tissues compared with the levels in paracarcinoma tissues.ConclusionWe screened and validated four autophagy-related genes associated with immune infiltration and prognosis in patients with HCC.

Albumin-Lymphocyte-Globulin-C-Reactive Protein Index as a Novel Prognostic Biomarker for Hepatocellular Carcinoma After Hepatectomy.

This study evaluated the performance of the albumin-lymphocyte-globulin-C-reactive protein (CRP) (ALGC) index as a novel prognostic biomarker for hepatocellular carcinoma (HCC) after hepatectomy. Patients (n=178) who underwent hepatectomy for HCC (July 2010 - December 2021) were analyzed. The ALGC index was calculated as [(albumin × lymphocyte) / (CRP × globulin × 104)]. Patients were divided into a low ALGC group (<1.82; n=81) and a high ALGC group (≥1.82; n=97). The association of the ALGC index with survival was assessed by univariate and multivariate analyses. The median overall survival (OS) was 100 (range: 1-149) months with 1-, 3-, and 5-year OS rates of 91.6%, 81.2%, and 64.2%, respectively. In univariate analysis, ALGC index (<1.82), alpha-fetoprotein (≥25 ng/mL), tumor size (≥3.5 cm), microvascular invasion, and multiple tumors were associated with shorter OS. ALGC index (<1.82) (hazard ratio [95% confidence interval]) (2.48 [1.407-4.513]; P=0.001) and multiple tumors (1.92 [1.070-3.356]; P=0.029) were independent predictors of OS in multivariate analysis. ALGC index is a novel prognostic biomarker for HCC after hepatectomy. It may assist in treatment stratification and better management of patients with HCC.

BCAR3 and BCAR3-related competing endogenous RNA expression in hepatocellular carcinoma and their prognostic value.

Hepatocellular carcinoma (HCC) is a malignant tumor that has a high incidence and mortality worldwide. Despite extensive studies, the detailed molecular mechanism of HCC development remains unclear. Studies have shown that the occurrence and development of HCC are closely related to abnormal gene expression. BCAR3 has been shown to be overexpressed in a variety of malignant tumors. However, the role of BCAR3 in HCC remains unclear. To investigate the expression of BCAR3 and BCAR3-related competing endogenous RNAs (ceRNAs) in HCC and their clinical significance, in order to provide new ideas for the diagnosis and treatment of HCC. The data of HCC were obtained from the Cancer Genome Atlas database and The Genotype Tissue Expression, including transcriptome data and clinical information. Multiple common databases, including UALCAN, Timer 2.0, cBioPortal, LinkedOmics, starBase, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, were used to analyse the expression of BCAR3, prognostic value, genetic alteration, co-expressed genes, differentially expressed genes, BCAR3 gene-related ceRNAs and functional enrichment analysis in HCC patients. Kaplan-Meier analysis, univariate and multivariate Cox regression analysis were used to analyze survival prognosis and the Spearman test was used to measure correlations between BCAR3 and immune functions. And R language package was used to analyze the correlation between BCAR3 and immune invasion of HCC. Our study indicated that BCAR3 was differentially expressed in various tumor tissues. The over-expression of BCAR3 gene was an unfavorable prognostic indicator for HCC patients, and associated with unfavorable cytogenetic risk and gene mutations. Moreover, most immune cells were positively correlated with BCAR3 (P < 0.05). According to the results of functional enrichment analysis, BCAR3 was involved in the positive regulation of epidermal growth factor receptor signaling pathway and ERBB signaling pathway, and was related to DNA replication and GTPase regulator activity. Finally, our study found that based on RAB30-DT and miR-19b-3p pathways, targeting BCAR3 might promote the occurrence and development of HCC. Collectively, this study indicated that the BCAR3 gene was involved in the occurrence and development of HCC, and it might be a new biomarker and therapeutic target for HCC, but the specific mechanism remains to be further verified.

CircATF6 inhibits hepatocellular carcinoma progression by suppressing calreticulin-mediated Wnt/β-catenin signaling pathway

Circular RNAs (circRNAs) are covalently closed, single-stranded RNAs that play critical roles in various biological processes and diseases, including cancers. However, the functions and mechanisms of circRNAs in hepatocellular carcinoma (HCC) need further clarification. Here, we identified and confirmed that circATF6 is downregulated in HCC tissues and negatively associated with the overall survival of HCC patients. Ectopic overexpression of circATF6 inhibits malignant phenotypes of HCC cells in vitro and in vivo, while knockdown of circATF6 had opposite effects. Mechanistically, we found that circATF6 bound to calreticulin (CALR) protein and acted as a scaffold to enhance the interaction of CALR with calpain2 (CAPN2), which promoted the degradation of CALR by its enzymatic activity. Moreover, we found that circATF6 inhibited HCC cells by suppressing CALR-mediated wnt/β-catenin signaling pathway. Taken together, our findings suggest that circATF6 is a potential prognostic biomarker and therapeutic target for HCC.

The obesity-related mutation gene on nonalcoholic fatty liver disease.

The prevalence of overweight and obesity is increasing, leading to metabolic-associated fatty liver disease (MAFLD) characterized by excessive accumulation of liver fat and a risk of developing hepatocellular carcinoma (HCC). The driver gene mutations may play the roles of passengers that occur in single 'hotspots' and can promote tumorigenesis from benign to malignant lesions. We investigated the impact of high body weight and BMI on HCC survival using The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset. To explore the effects of obesity-related gene mutations on HCC, we collected driver mutation genes in 34 TCGA patients with BMI ≥ 27 and 23 TCGA patients with BMI < 27. The digital PCR performing the PBMC samples for the variant rate by clinical cohort of 96 NAFLD patients. Our analysis showed that obesity leads to significantly worse survival outcomes in HCC. Using cbioportal, we identified 414 driver mutation genes in patients with obesity and 127 driver mutation genes in non-obese patients. Functional analysis showed that obese-related genes significantly enriched the regulated lipid and insulin pathways in HCC. The insulin secretion pathway in patients with obesity HCC-specific survival identified ABCC8 and PRKCB as significant genes (p < 0.001). It revealed significant differences in gene mutation and gene expression profiles compared to non-obese patients. The digital PCR test ABCC8 variants were detected in PBMC samples and caused a 14.5% variant rate, significantly higher than that of non-obese NAFLD patients. The study findings showed that the gene ABCC8 was a patient with the obesity-related gene in NAFLD, which provides the probability that ABCC8 mutation contributes to the pre-cancer lesion biomarker for HCC.

Phase separation of RNF214 promotes the progression of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, and the expression and function of an uncharacterized protein RNF214 in HCC are still unknown. Phase separation has recently been observed to participate in the progression of HCC. In this study, we investigated the expression, function, and phase separation of RNF214 in HCC. We found that RNF214 was highly expressed in HCC and associated with poor prognosis. RNF214 functioned as an oncogene to promote the proliferation, migration, and metastasis of HCC. Mechanically, RNF214 underwent phase separation, and the coiled-coil (CC) domain of RNF214 mediated its phase separation. Furthermore, the CC domain was necessary for the oncogenic function of RNF214 in HCC. Taken together, our data favored that phase separation of RNF214 promoted the progression of HCC. RNF214 may be a potential biomarker and therapeutic target for HCC.

The Value of CEUS LI-RADS combined with AFP in early diagnosis of hepatocellular carcinoma in low- and high-risk patients.

We found that the occurrence of hepatocellular carcinoma (HCC) has increased significantly in non-cirrhotic individuals, with HCC being frequently overlooked or misdiagnosed. Contrast-enhanced ultrasound (CEUS) Liver Imaging Reporting and Data System (LI-RADS) is known to have a high diagnostic quality in high-risk HCC patients. Therefore, we aimed to compare the detection accuracy of CEUS LI-RADS for HCC between low- and high-risk individuals, to confirm its value in low-risk patients at increased risk of HCC, but not yet included in the high-risk groups of LI-RADS. In addition, since CEUS LR-4 and LR-M categories contain a relatively high proportion of HCC, and serum alpha-fetoprotein (AFP) is the most commonly used biomarker for HCC, and the clinically valid, we attempted to further improve the early diagnostic capability of CEUS LI-RADS for HCC in the low-risk and high-risk patients by combining CEUS LR-4 and LR-M categories with AFP. We defined high-risk groups (HR)-included in the high-risk patients of LI-RADS, low-risk groups (LR)-not included in the high-risk patients of LI-RADS and enrolled 189 HCC patients with LR and HR settings in a retrospective study. All lesions were confirmed histopathologically. The CEUS LI-RADS accuracy for detecting HCC in these two patients was compared. In addition, the diagnostic algorithm in our study was proposed (for CEUS LR-4 and LR-M patients with AFP>20 ng/ml). we analyzed the ability of CEUS LI-RADS as a valid method of establishing the early diagnosis of HCC in LR and HR patients by combining LR-4 and LR-M categories with AFP. Through comparative analysis, the specificity of the CEUS LR-5 category for HCC in the HR group was 78.4%, whereas in the LR group, it was 94.2%. Meanwhile, the sensitivity (63.2% vs. 63.0%) and positive predictive value (PPV) (75.0% vs. 88.7%) did not differ between the LR and HR groups (P = 0.990, P = 0.299). It is noteworthy that there were the high proportion of HCC in CEUS LR-4 and LR-M categories in our cases and when we combined CEUS LR-4 and LR-M categories with AFP significantly improved the sensitivity by 21.0% (84.2%) in the LR group, and by 16.0% (79.0%) in the HR group, with statistically difference in sensitivity after combination in the HR group (P = 0.014). The CEUS LR-5 category has real meaningful utility in the diagnosis of HCC in both LR and HR patients. The early detection power of the CEUS LI-RADS category for HCC patients was further increased when the CEUS LR-4 and LR-M categories were combined with elevated AFP.

Acyl-CoA Synthetase Medium-Chain Family Member 5–Mediated Fatty Acid Metabolism Dysregulation Promotes the Progression of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver cancer, with high incidence and mortality worldwide. Despite diagnostic and therapeutic advancements, HCC remains poorly responsive to treatment with a poor prognosis. Understanding the molecular mechanisms driving HCC is crucial for developing effective therapies. Emerging evidence indicates that dysregulated fatty acid metabolism contributes to HCC. Acyl-CoA medium-chain synthetase 5 (ACSM5), involved in fatty acid metabolism, is downregulated in HCC, however, its role is not well understood. In the study, we analyzed ACSM5 expression in HCC patient samples and cell lines. Using newly established ACSM5-overexpressing HCC cell lines, Huh7-ACSM5 and Hepa1-6-ACSM5, we investigated the effects and regulatory mechanisms of ACSM5. Our results showed that ACSM5 was significantly downregulated in HCC tumor tissues compared to non-tumor tissues. ACSM5 expression was regulated by DNA methylation, with a DNMT1 inhibitor effectively increasing ACSM5 expression and reducing promoter region methylation. Overexpression of ACSM5 in Huh7 cells reduced fatty acid accumulation, decreased cell proliferation, migration, and invasion in vitro, and inhibited tumor growth in mouse xenografts. Furthermore, ACSM5 overexpression also decreased STAT3 phosphorylation, subsequently affecting downstream cytokine TGFB and FGF12 mRNA levels. Our findings suggest that ACSM5 downregulation contributes to HCC progression, providing insights into its oncogenic role and highlighting its potential as a biomarker and therapeutic target for HCC.

Serum S-adenosylhomocysteine, rather than homocysteine, is associated with hepatocellular carcinoma survival: a prospective cohort study

BackgroundEmerging evidence suggested that S-adenosylhomocysteine (SAH) may be a better serum biomarker for cardiovascular disease than homocysteine (Hcy). However, the role of SAH in hepatocellular carcinoma (HCC) prognosis remains unclear. ObjectivesWe aimed to prospectively explore the relationships between serum SAH and related metabolites (Hcy, S-adenosylmethionine [SAM]) with HCC survival, and to evaluate the effect modifications by gene polymorphisms in one-carbon metabolism key enzymes. MethodsWe included 1,080 newly diagnosed HCC patients from the Guangdong Liver Cancer Cohort. Serum SAH, Hcy, and SAM were measured utilizing HPLC-MS/MS. Gene polymorphisms in one-carbon metabolism key enzymes were identified using competitive allele-specific PCR (KASP). Primary outcomes were liver cancer-specific survival (LCSS) and overall survival (OS). Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using multivariate Cox proportional hazards models. ResultsAfter a median follow-up of 3.6 years, 601 deaths occurred, with 552 (92%) attributed to HCC. Multivariable analysis revealed that patients in the highest quartile of serum SAH concentrations were significantly associated with worse survival compared to those in the lowest quartile, with HRs of 1.58 (95% CI: 1.19, 2.10; P-trend = 0.002) for LCSS and 1.54 (95% CI: 1.18, 2.02; P-trend = 0.001) for OS. There were no significant interactions between serum SAH concentrations and genetic variants of one-carbon metabolism key enzymes. No significant associations were found between serum Hcy, SAM concentrations and SAM/SAH ratio with LCSS or OS. ConclusionsHigher serum SAH concentrations, rather than homocysteine, were independently associated with worse survival in HCC patients, regardless of the genetic variants of one-carbon metabolism key enzymes. These findings suggesting that SAH may serve as a novel metabolism-related prognostic biomarker for HCC.

Bioinformatics prediction and experimental verification identify a cuproptosis-related gene signature as prognosis biomarkers of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) of which its prognostic prediction is still unclarified is a highly heterogeneous disease. Cuproptosis is a form of cell death that depends on copper regulation. Whether the cuproptosis-related genes can be the prognostic indicators of HCC is yet to be elucidated. The aim of this study is to investigate whether cuproptosis-related genes play a role in HCC and can be used as a diagnostic index to predict the occurrence of liver cancer. We downloaded HCC patients' gene expression profiles and their corresponding clinical data from a public database. To screen data, we used single factor Cox regression analysis, meanwhile, polymerase chain reaction (PCR) was used for the verification. After that, the risk score was calculated and the relationship between risk score and clinical factors was analyzed. Besides, a nomogram map was constructed for predicting the prognosis of HCC, and calibration map and decision curve analysis (DCA) map were used to test the model. Compared to the high expression group of four cuproptosis-related genes, the low expression group showed better overall survival (OS) [hazard ratio (HR) =2.58; 95% confidence interval (CI): 1.72-3.89, P<0.01]. The expression of the four cuproptosis-relate genes increased in liver cancer cell lines compared to liver cell lines (P<0.05). Based on these four genes, we calculated the risk score and divided them into two groups as high-risk group and low-risk group. The risk factor map showed the high-risk group had shorter survival time and the four genes were highly expressed. The area under curve (AUC) of receiver operating characteristic (ROC) prediction curve for the first year was 0.726. Risk scores were closely related to clinical factors and immune cells. Finally, we constructed a nomogram for predicting the prognosis of HCC. The risk score for cuproptosis-related genes was established and involved in the construction of the nomogram, providing a new perspective on the prognosis and copper metabolism of HCC.

UBE2S promotes glycolysis in hepatocellular carcinoma by enhancing E3 enzyme-independent polyubiquitination of VHL.

Ubiquitination is widely involved in the progression of hepatocellular carcinoma (HCC) by regulating various cellular processes. However, systematic strategies for screening core ubiquitin-related genes, clarifying their functions and mechanisms, and ultimately developing potential therapeutics for patients with HCC are still lacking. Cox and LASSO regression analyses were performed to construct a ubiquitin-related gene prediction model for HCC. Loss- and gain-of-function studies, transcriptomic and metabolomics analysis were used to explore the function and mechanism of UBE2S on HCC cell glycolysis and growth. Based on 1423 ubiquitin-related genes, a four-gene signature was successfully constructed to evaluate the prognosis of patients with HCC. UBE2S was identified in this signature with the potential to predict the survival of patients with HCC. E2F2 transcriptionally upregulated UBE2S expression by directly binding to its promoter. UBE2S positively regulated glycolysis in a HIF-1α-dependent manner, thus promoting the proliferation of HCC cells. Mechanistically, UBE2S enhanced K11-linkage polyubiquitination at lysine residues 171 and 196 of VHL independent of E3 ligase, thereby indirectly stabilizing HIF-1α protein levels by mediating the degradation of VHL by the proteasome. In particular, the combination of cephalomannine, a small molecule compound that inhibits the expression of UBE2S, and PX-478, an inhibitor of HIF-1α, significantly improved the anti-tumor efficacy. UBE2S is identified as a key biomarker in HCC among the thousands of ubiquitin-related genes and promotes glycolysis by E3 enzyme-independent ubiquitination, thus serving as a therapeutic target for the treatment of HCC.

Tumor budding is a meaningful prognostic marker in patients with hepatocellular carcinoma after curative hepatectomy

AbstractAimTumor budding (TB) has excellent prognostic value in many solid tumors, but there is little research on it in hepatocellular carcinoma (HCC). This study assessed the prognostic value of TB in patients with HCC who received hepatectomy.MethodsThis retrospective study included 210 patients with HCC who received curative hepatectomy at the First Affiliated Hospital of Xi'an Jiaotong University, between 2016 and 2018. TB was evaluated on hematoxylin‐ and eosin‐stained slides according to the criteria established by the 2016 International Tumor Budding Consensus Conference. t‐tests, Chi‐squared tests, and rank‐sum tests were used to correlate the extent of TB with clinicopathological parameters. Prognostic analysis was performed using Cox regression models and the Kaplan–Meier method.ResultsThe positive detection rate of TB was 45.2% (95/210) in 210 patients with HCC. Patients positive for TB always exhibit lower tumor differentiation, higher hepatitis B virus DNA levels, and more severe liver fibrosis. Multivariate Cox analysis identified TB (hazard ratio [HR]: 2.232, 95% confidence interval [CI]: 1.479–3.368, p &lt; 0.001) as an independent prognostic factor for patients' recurrence‐free survival (RFS), similar to tumor size (HR: 1.070, 95% CI: 1.070–1.142, p = 0.042) and satellite nodule (HR: 2.266, 95% CI: 1.298–3.956, p = 0.004). Kaplan–Meier analysis also demonstrated that TB‐positive patients had a significantly worse RFS. Interestingly, subgroup analysis revealed that among HCC patients with negative microvascular invasion (MVI), TB was also strongly associated with RFS (HR: 3.206, 95% CI: 1.667–6.168, p &lt; 0.001). These findings suggest that TB may serve as a supplemental prognostic biomarker for HCC‐negative MVI.ConclusionsTB is an adverse prognostic biomarker for HCC, particularly in patients negative for MVI. TB evaluation should be considered in the postoperative pathological examination of HCC in clinical practice.

A new label free spiral sensor using impedance spectroscopy to characterize hepatocellular carcinoma in tissue and serum samples

Hepatocellular carcinoma (HCC) stands as the most prevalent form of primary liver cancer, predominantly affecting patients with chronic liver diseases such as hepatitis B or C-induced cirrhosis. Diagnosis typically involves blood tests (assessing liver functions and HCC biomarkers), imaging procedures such as Computed Tomography (CT) and Magnetic Resonance Imaging (MRI), and liver biopsies requiring the removal of liver tissue for laboratory analysis. However, these diagnostic methods either entail lengthy lab processes, require expensive imaging equipment, or involve invasive techniques like liver biopsies. Hence, there exists a crucial need for rapid, cost-effective, and noninvasive techniques to characterize HCC, whether in serum or tissue samples. In this study, we developed a spiral sensor implemented on a printed circuit board (PCB) technology that utilizes impedance spectroscopy and applied it to 24 tissues and sera samples as proof of concept. This newly devised circuit has successfully characterized HCC and normal tissue and serum samples. Utilizing the distinct dielectric properties between HCC cells and serum samples versus the normal samples across a specific frequency range, the differentiation between normal and HCC samples is achieved. Moreover, the sensor effectively characterizes two HCC grades and distinguishes cirrhotic/non-cirrhotic samples from tissue specimens. In addition, the sensor distinguishes cirrhotic/non-cirrhotic samples from serum specimens. This pioneering study introduces Electrical Impedance Spectroscopy (EIS) spiral sensor for diagnosing HCC and liver cirrhosis in clinical serum—an innovative, low-cost, rapid (< 2 min), and precise PCB-based technology without elaborate sample preparation, offering a novel non-labeled screening approach for disease staging and liver conditions.

Multiomics Analysis of Interleukin-21 as a Potential Immunologic and Biomarker in Hepatocellular Carcinoma.

Interleukin-21 (IL-21) is an important antitumor cytokine that contributes to the proliferation and differentiation of CD8+ T cells. It has been proven to enhance the response to immune checkpoint inhibitors (ICIs) in various solid tumors. However, its role in hepatocellular carcinoma (HCC) has not yet been clarified. In this research, we aimed to investigate the antitumor effect of IL-21 in HCC and its effect on ICI treatment. Through transcriptome sequencing analysis and immunohistochemistry validation, we found that patients with high IL-21 expression had a better prognosis. HCCs with high expression of IL-21 had higher infiltration of CD8+ T cells, increased expression of immune checkpoints, and an improved response to ICI treatment. In conclusion, IL-21 can enhance the efficacy of ICI treatment and improve the prognosis of patients by promoting the infiltration of CD8+ T cells and the expression of immune checkpoint-related genes.

Integrated Bioinformatic Analysis Reveals the Oncogenic, Survival, and Prognostic Characteristics of TPX2 in Hepatocellular Carcinoma.

Targeting protein for Xenopus kinesin-like protein 2 (TPX2), a well-known mitotic protein, has been linked to carcinogenesis in several cancers. This study investigated the role of TPX2 in hepatocellular carcinoma (HCC) from various aspects using bioinformatic analyses. TPX2 expression and its prognostic value in pan-cancers were analyzed using SangerBox. TPX2 expression and its association with prognosis, immune infiltration, tumor mutations, and signaling pathways in HCC were analyzed using UALCAN, BoxKaplan-Meier Plotter, GEPIA, Human Protein Atlas, TIMER 2.0, and SangerBox. Genes co-expressed with TPX2 in HCC were analyzed using the HCCDB database, followed by functional enrichment using SangerBox. Clinical predictive models were established based on TPX2 and its co-expressed genes using the ACLBI database. TPX2 expression significantly increased in pan-cancers and was associated with survival in nearly half of the cancer types. High TPX2 expression has been linked to poor survival outcomes in patients with HCC. TPX2 expression was positively correlated with abundant infiltration of immune cells (including B cells, CD4 + /CD8 + T cells, macrophages, neutrophils, and dendritic cells), TP53 mutation, and carcinogenesis-related pathways, such as the PI3K/AKT/mTOR pathway, cellular response to hypoxia, and tumor proliferation signature. Nineteen genes were found to be co-expressed with TPX2 in HCC, and these genes showed close positive correlations and were mainly implicated in cell cycle-related functions. A prognostic model established using TPX2 and its expressed genes could stratify HCC patients into high- and low-risk groups, with a significantly shorter survival time in high-risk groups. The prognostic model performed well in predicting 1-, 3-, and 5-year survival of patients with HCC, with areas under the curve of 0.801, 0.725, and 0.711, respectively. TPX2 functions as an oncogene in HCC, and its high expression is detrimental to the survival of patients with HCC. Thus, TPX2 may be a prognostic biomarker and potential therapeutic target for HCC.