Hepatocellular Carcinoma Status Research Articles

LTR retrotransposon-derived LncRNA LINC01446 promotes hepatocellular carcinoma progression and angiogenesis by regulating the SRPK2/SRSF1/VEGF axis

The causal link between long terminal repeat (LTR) retrotransposon-derived lncRNAs and hepatocellular carcinoma (HCC) remains elusive and whether these cancer-exclusive lncRNAs contribute to the effectiveness of current HCC therapies is yet to explore. Here, we investigated the activation of LTR retrotransposon-derived lncRNAs in a broad range of liver diseases. We found that LTR retrotransposon-derived lncRNAs are mainly activated in HCC and is correlated with the proliferation status of HCC. Furthermore, we discovered that an LTR retrotransposon-derived lncRNA, LINC01446, exhibits specific expression in HCC. HCC patients with higher LINC01446 expression had shorter overall survival times. In vitro and in vivo assays showed that LINC01446 promoted HCC growth and angiogenesis. Mechanistically, LINC01446 bound to serine/arginine protein kinase 2 (SRPK2) and activated its downstream target, serine/arginine splicing factor 1 (SRSF1). Furthermore, activation of the SRPK2-SRSF1 axis increased the splicing and expression of VEGF isoform A165 (VEGFA165). Notably, inhibiting LINC01446 expression dramatically impaired tumor growth in vivo and resulted in better therapeutic outcomes when combined with antiangiogenic agents. In addition, we found that the transcription factor MESI2 bound to the cryptic MLT2B3 LTR promoter and drove LINC01446 transcription in HCC cells. Taken together, our findings demonstrate that LTR retrotransposon-derived LINC01446 promotes the progression of HCC by activating the SRPK2/SRSF1/VEGFA165 axis and highlight targeting LINC01446 as a potential therapeutic strategy for HCC patients.

Nomogram prediction of vessels encapsulating tumor clusters in small hepatocellular carcinoma ≤ 3 cm based on enhanced magnetic resonance imaging.

Vessels encapsulating tumor clusters (VETC) represent a recently discovered vascular pattern associated with novel metastasis mechanisms in hepatocellular carcinoma (HCC). However, it seems that no one have focused on predicting VETC status in small HCC (sHCC). This study aimed to develop a new nomogram for predicting VETC positivity using preoperative clinical data and image features in sHCC (≤ 3 cm) patients. To construct a nomogram that combines preoperative clinical parameters and image features to predict patterns of VETC and evaluate the prognosis of sHCC patients. A total of 309 patients with sHCC, who underwent segmental resection and had their VETC status confirmed, were included in the study. These patients were recruited from three different hospitals: Hospital 1 contributed 177 patients for the training set, Hospital 2 provided 78 patients for the test set, and Hospital 3 provided 54 patients for the validation set. Independent predictors of VETC were identified through univariate and multivariate logistic analyses. These independent predictors were then used to construct a VETC prediction model for sHCC. The model's performance was evaluated using the area under the curve (AUC), calibration curve, and clinical decision curve. Additionally, Kaplan-Meier survival analysis was performed to confirm whether the predicted VETC status by the model is associated with early recurrence, just as it is with the actual VETC status and early recurrence. Alpha-fetoprotein_lg10, carbohydrate antigen 199, irregular shape, non-smooth margin, and arterial peritumoral enhancement were identified as independent predictors of VETC. The model incorporating these predictors demonstrated strong predictive performance. The AUC was 0.811 for the training set, 0.800 for the test set, and 0.791 for the validation set. The calibration curve indicated that the predicted probability was consistent with the actual VETC status in all three sets. Furthermore, the decision curve analysis demonstrated the clinical benefits of our model for patients with sHCC. Finally, early recurrence was more likely to occur in the VETC-positive group compared to the VETC-negative group, regardless of whether considering the actual or predicted VETC status. Our novel prediction model demonstrates strong performance in predicting VETC positivity in sHCC (≤ 3 cm) patients, and it holds potential for predicting early recurrence. This model equips clinicians with valuable information to make informed clinical treatment decisions.

Exposure of Bisphenols (BPs) to hepatocellular carcinoma (HCC) patients and non-HCC patients: Association with liver function biomarkers

Bisphenols (BPs), prevalent endocrine disruptors in daily life, have been widely studied in vitro for their potential to cause liver diseases, including liver cancer. However, there is a dearth of research exploring BP levels in clinical populations with liver issues. This study comprehensively analyzed the distribution and characteristics of ten BPs in paired serum, blood, and urine samples from 197 hepatocellular carcinoma (HCC) patients and 100 non-HCC patients. The study investigated the impact of sociodemographic factors, such as gender, BMI (Body Mass Index), age, drinking, and smoking habits, on BP distribution. Additionally, it analyzed the relationship between BPs and three liver function biomarkers: γ-glutamyl transferase (GGT), alanine aminotransferase (ALT) and alpha-fetoprotein (AFP). Notably, some BP levels were higher in non-HCC patients compared to HCC patients across all three sample types. For HCC patients, the BP concentrations followed the order of serum (29.12 ng/mL) > blood (18.36 ng/mL) > urine (14.91 ng/mL), whereas for non-HCC patients, the order was urine (30.79 ng/mL) > serum (29.51 ng/mL) > blood (24.34 ng/mL). Moreover, BP levels in all patient samples, regardless of HCC status, increased with age. Among HCC patients, females were found to have a higher exposure to BPs compared to males, while the opposite trend was observed in non-HCC patients. Furthermore, the study revealed positive correlations between BPs and liver function indicators, such as ALT and BPAF, BPAP, BPBP; GGT and BPF; and AFP and BPF. These findings suggest a potential association between BPs and liver disease. This comprehensive analysis of BP concentrations in bio-samples from liver disease patients provides valuable insights into the relationship between BPs and liver disease in clinical settings, serving as a reference for future research and clinical practice.

Role of CCR1/5/7 in hepatocellular carcinoma: a study on prognostic evaluation, molecular subtyping, and association with immune infiltration.

This study aims to assess the prognostic value of the C-C motif chemokine receptor (CCR) gene family in hepatocellular carcinoma (HCC) and its relationship with immune infiltration and molecular subtypes of HCC. The evaluation of the GSE14520 dataset and TCGA database confirmed the prognostic significance of CCR. Building upon the correlation between CCR1, CCR5, and CCR7 and favorable prognosis, we further validated the prognostic importance of CCR1, CCR5, and CCR7 in ICGC database and an independent cohort from Guangxi autonomous region. Then, we constructed a risk prognosis model. Additionally, we observed significant positive correlations between CCR1, CCR5, and CCR7 and the infiltration of B cells, T cells, and macrophages in HCC. Subsequently, we conducted CCK assays, Transwell assays, and colony formation assays to evaluate the molecular biological functions of CCR1, CCR5, and CCR7. These experiments further confirmed that upregulation of CCR1, CCR5, and CCR7 can individually inhibit the proliferation, migration, and stemness of HCC cells. By analyzing the relationship between expression levels and tumor mutation frequency, we discovered that patients with high CCR1 expression were more likely to be classified as non-proliferative HCC. Similar conclusions were observed for CCR5 and CCR7. The association of CCR1, CCR5, and CCR7 with the molecular subtypes of HCC suggests that they may serve as intermediary molecules linking immune status and molecular subtypes in HCC. In summary, CCR1, CCR5, and CCR7 have the potential to serve as prognostic biomarkers for HCC and regulate HCC progression by influencing immune cell infiltration.

PRMT5 Mediated HIF1α Signaling and Ras-Related Nuclear Protein as Promising Biomarker in Hepatocellular Carcinoma.

Protein arginine N-methyltransferase 5 (PRMT5) has been identified as a potential therapeutic target for various cancer types. However, its role in regulating the hepatocellular carcinoma (HCC) transcriptome remains poorly understood. In this study, publicly available databases were employed to investigate PRMT5 expression, its correlation with overall survival, targeted pathways, and genes of interest in HCC. Additionally, we utilized in-house generated NGS data to explore PRMT5 expression in dysplastic nodules compared to hepatocellular carcinoma. Our findings revealed that PRMT5 is significantly overexpressed in HCC compared to normal liver, and elevated expression correlates with poor overall survival. To gain insights into the mechanism driving PRMT5 overexpression in HCC, we analyzed promoter CpG islands and methylation status in HCC compared to normal tissues. Pathway analysis of PRMT5 knockdown in the HCC cells revealed a connection between PRMT5 expression and genes related to the HIF1α pathway. Additionally, by filtering PRMT5-correlated genes within the HIF1α pathway and selecting up/downregulated genes in HCC patients, we identified Ras-related nuclear protein (RAN) as a target associated with overall survival. For the first time, we report that PRMT5 is implicated in the regulation of HIF1A and RAN genes, suggesting the potential prognostic utility of PRMT5 in HCC.

Abstract 4802: Accuracy of the GALAD serologic model in the diagnosis of hepatocellular carcinoma in Ghanaian patients

Abstract Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. In sub-Saharan Africa, HCC is the second most common cancer in men and the sixth in women. African patients present with HCC at a young age and at advanced stage of disease. Improved surveillance can increase early HCC detection. The GALAD score has good sensitivity in the diagnosis of HCC in Asia, Europe and North America, however, it has not been validated in an African cohort. The aim of this study was to assess the performance of the GALAD score in the diagnosis of HCC in Ghanaian patients. Methods: Clinical data from patients with cirrhosis (n=93) or HCC (n=78) from out-patient hepatology clinics at 3 teaching hospitals in Ghana were abstracted, and serum samples analyzed. A logistic regression model predicting HCC status based on GALAD score was constructed to obtain the Receiver Operating Characteristics (ROC) curve for GALAD. The area under the curve (AUC) with 95% confidence interval was calculated and used to assess the performance of the GALAD score in surveillance for HCC. Results: The median AFP (5010.2 vs. 3.4), L3% (28.3 vs. 0.3) and DCP (507.6 vs. 0.2) levels were all significantly higher among HCC cases than the controls (p<0.0001). The median GALAD score was also higher among HCC patients (8.0 vs. -4.1, p<0.0001). The AUC of the GALAD score in the diagnosis of HCC was 0.86 (95% CI 0.79 - 0.92). At a cut-off value of -0.37, the GALAD score had a sensitivity of 0.81 and a specificity of 0.86. In a re-fit of the logistic regression model, the most significant factors in the GALAD model in our cohort were AFP-L3% and log(DCP). The AUC of the new GALAD model after model selection was 0.89. Conclusion: The GALAD score can be used to detect HCC in Ghana and has the potential to improve HCC surveillance in low-resource settings in sub-Saharan Africa. Citation Format: Yvonne Ayerki Nartey, Ju Dong Yang, Tyler Zemla, Joshua Ayawin, Shadrack Osei Asibey, Mohamed El-Kassas, Sally Afua Bampoh, Amoako Duah, Adwoa Agyei-Nkansah, Yaw Asante Awuku, Mary Yeboah Afihene, Hiroyuki Yamada, Jun Yin, Amelie Plymoth, Lewis Rowland Roberts. Accuracy of the GALAD serologic model in the diagnosis of hepatocellular carcinoma in Ghanaian patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4802.

Preoperatively predicting vessels encapsulating tumor clusters in hepatocellular carcinoma: Machine learning model based on contrast-enhanced computed tomography.

Recently, vessels encapsulating tumor clusters (VETC) was considered as a distinct pattern of tumor vascularization which can primarily facilitate the entry of the whole tumor cluster into the bloodstream in an invasion independent manner, and was regarded as an independent risk factor for poor prognosis in hepatocellular carcinoma (HCC). To develop and validate a preoperative nomogram using contrast-enhanced computed tomography (CECT) to predict the presence of VETC+ in HCC. We retrospectively evaluated 190 patients with pathologically confirmed HCC who underwent CECT scanning and immunochemical staining for cluster of differentiation 34 at two medical centers. Radiomics analysis was conducted on intratumoral and peritumoral regions in the portal vein phase. Radiomics features, essential for identifying VETC+ HCC, were extracted and utilized to develop a radiomics model using machine learning algorithms in the training set. The model's performance was validated on two separate test sets. Receiver operating characteristic (ROC) analysis was employed to compare the identified performance of three models in predicting the VETC status of HCC on both training and test sets. The most predictive model was then used to constructed a radiomics nomogram that integrated the independent clinical-radiological features. ROC and decision curve analysis were used to assess the performance characteristics of the clinical-radiological features, the radiomics features and the radiomics nomogram. The study included 190 individuals from two independent centers, with the majority being male (81%) and a median age of 57 years (interquartile range: 51-66). The area under the curve (AUC) for the combined radiomics features selected from the intratumoral and peritumoral areas were 0.825, 0.788, and 0.680 in the training set and the two test sets. A total of 13 features were selected to construct the Rad-score. The nomogram, combining clinical-radiological and combined radiomics features could accurately predict VETC+ in all three sets, with AUC values of 0.859, 0.848 and 0.757. Decision curve analysis revealed that the radiomics nomogram was more clinically useful than both the clinical-radiological feature and the combined radiomics models. This study demonstrates the potential utility of a CECT-based radiomics nomogram, incorporating clinical-radiological features and combined radiomics features, in the identification of VETC+ HCC.

Characterization of m6A RNA methylation mediated immune heterogeneity and functional validation in hepatocellular carcinoma.

N6 -methyladenosine (m6 A) mediates RNA modification in various biological processes. It plays a key role in hepatocellular carcinoma (HCC) through regulating methyltransferase. The present study aims to analyze the correlation between the m6 A and the immune status of HCC, and to construct an m6 A-related prognostic signature for HCC. HCC subtypes with different m6 A modification activities were identified based on the m6 A-related genes. Lasso Cox regression was applied to construct an m6 A-related prognostic model for HCC. Then, the prognostic potential of the constructed signature was evaluated and validated in the external validation dataset. Small interfering RNAs were designed to knockdown FBXO5. CCK-8 assay, Edu staining, wound healing assay, and Transwell cell invasion assay were used to detect cell proliferation, migration, and invasion ability. Two m6 A-related HCC subtypes were identified. The m6 A modification active group showed an immune suppressive microenvironment compared to the m6 A modification inactive group. The differentially expressed genes (DEGs) between the HCC subtypes were screened. Enrichment analysis was performed using the DEGs. Subsequently, an m6 A-related prognostic model was established. The prognostic model performed well in both training and validation datasets. Moreover, knockdown of FBXO5, one of the genes in the prognostic model, inhibited the proliferation, migration, and invasion of HepG2 cells. The heterogeneity of m6 A RNA methylation is associated with immune status in HCC. The constructed m6 A-related gene-based signature can predict the prognosis of HCC patients. The genes in the prognostic model also have therapeutic potential for HCC.

Hepatocellular carcinoma and aflatoxin in Sudan: The way forward

Hepatocellular carcinoma (HCC) is the sixth most common type of cancer and the third leading cause of death worldwide. It is especially prevalent in developing countries, with around 80% of cases occurring in Asia and Africa. Aflatoxin B1 is a well-documented risk factor for HCC, among other factors. In Sudan, there is limited reliable and comprehensive data on cancer epidemiology, including HCC. This paper focuses on the current status of HCC in Sudan, specifically in relation to aflatoxin. Additionally, recommendations are provided to enhance the control measures for HCC in the country.

Global trends and hotspots in the field of mitochondrial dynamics and hepatocellular carcinoma: A bibliometric analysis from 2007 to 2023

BackgroundMitochondria are dynamic organelles, and mitochondrial dynamics are important for the maintenance of mitochondrial inheritance and function. Recently, an increasing number of studies have shown that mitochondrial dynamics play an important role in the occurrence and development of hepatocellular carcinoma (HCC). However, bibliometric analyses of mitochondrial dynamics in HCC are scarce. Therefore, we conducted a bibliometric analysis to explore the current global research status and trends in mitochondrial dynamics and HCC. MethodsGlobal publications on mitochondrial dynamics and HCC published between 2007 and May 2023 were retrieved from the Web of Science Core Collection (WoSCC) database. Bibliometric analysis was performed using Bibliometrix, VOSviewer, and CiteSpace to analyze the numbers, citations, countries, institutions, authors, journals, references, and keywords. ResultsA total of 518 publications were retrieved fromthe WoSCC database. China and The Fourth Military Medical University were the most productive countries and institutions. Zorzano, A published the most literature whereas Chen, HC was the author with the highest number of co-citations. Plos One was the most popular journal, whereas the Journal of Biological Chemistry had the highest number of co-citations. The most frequently used keyword was “mitochondria”. Further analysis of the references and keywords showed that the molecular mechanisms linking them to drug therapy targets should be the focus of future studies. ConclusionsResearch on mitochondrial dynamics in HCC has received much attention, and many studies have been published. However, research on mitochondrial dynamics and HCC has been limited by insufficient regional development imbalances and global cooperation. Nevertheless, future research on mitochondrial dynamics and HCC is promising, especially regarding the molecular mechanisms of mitochondrial fission and fusion and how to link the currently known molecular mechanisms with drug therapy targets for HCC.

Association of Serum Alpha-fetoprotein with the Tumor Characters and HBV Status of Hepatocellular Carcinoma to Assess its Resectability

Background: Serum alpha-fetoprotein (AFP) has long been used to complement imaging tests in the screening and diagnosis of hepatocellular carcinoma (HCC), its utility as a predictive marker of long-term risk for HCC in HBV patients is contentious. Objective: The current study is aimed to assess the serum alpha-fetoprotein with the tumor character and HBV status of HCC to assess its resectability. Methods: This was a single-center, cross-sectional study done from September 2020 to August 2021 at the department of Hepatobiliary, pancreatic, and liver transplantation surgery at BSMMU. A total of 27 HCC patients who met the inclusion criteria were enrolled in the study. Clinical, laboratory, and imaging findings were obtained using a standardized data collecting sheet with the patients' informed agreement. AFP was measured by automated chemiluminescence analyzer (LIAISON XL, DiaSorin, Italy) in the Department of Biochemistry & Molecular Biology, BSMMU. Statistical analyses were performed using SPSS version 22. Quantitative variables were expressed as mean standard deviation and examined using an unpaired t-test. The qualitative data were represented by frequencies and percentages, and the Chi-Square test and Fisher exact test (where applicable) were used to determine any association. The statistical tests were conducted with a 95% confidence interval, and P<0.05 was deemed statistically significant. Results: Majority of the tumors were single and located in the right lobe. Local extension and distant metastasis were preset in unresectable patients of group 2.Hepatitis B virus was positive in 16 (59.3%) patients and DNA was detectable in 8 (29.6%) patients. HBV positivity and detectable HBV DNA was significantly associated with poor resectable status in group 2 but insignificant in group 1. Conclusions: In this study, the overall resectability was 37%. HBV positive HCC patients are significantly associated with poor resectability when serum AFP is raised and it would be more indicative when HBV DNA is detected. TAJ 2023; 36: No-2: 111-119

Impact of Median MELD at Transplant Minus 3 National Policy on Quality of Transplanted Livers for Patients With and Without Hepatocellular Carcinoma.

Patients with hepatocellular carcinoma (HCC) have been overprioritized in the deceased donor liver allocation system. The United Network for Organ Sharing adopted a policy in May 2019 that limited HCC exception points to the median Model for End-Stage Liver Disease at transplant in the listing region minus 3. We hypothesized this policy change would increase the likelihood to transplant marginal quality livers into HCC patients. This was a retrospective cohort study of a national transplant registry, including adult deceased donor liver transplant recipients with and without HCC from May 18, 2017, to May 18, 2019 (prepolicy) to May 19, 2019, to March 1, 2021 (postpolicy). Transplanted livers were considered of marginal quality if they met ≥1 of the following: (1) donation after circulatory death, (2) donor age ≥70, (3) macrosteatosis ≥30% and (4) donor risk index ≥95th percentile. We compared characteristics across policy periods and by HCC status. A total of 23 164 patients were included (11 339 prepolicy and 11 825 postpolicy), 22.7% of whom received HCC exception points (prepolicy versus postpolicy: 26.1% versus 19.4%; P = 0.03). The percentage of transplanted donor livers meeting marginal quality criteria decreased for non-HCC (17.3% versus 16.0%; P < 0.001) but increased for HCC (17.7% versus 19.4%; P < 0.001) prepolicy versus postpolicy. After adjusting for recipient characteristics, HCC recipients had 28% higher odds of being transplanted with marginal quality liver independent of policy period (odds ratio: 1.28; confidence interval, 1.09-1.50; P < 0.01). The median Model for End-Stage Liver Disease at transplant in the listing region minus 3 policy limited exception points and decreased the quality of livers received by HCC patients.

Development and validation a radiomics nomogram for predicting thymidylate synthase status in hepatocellular carcinoma based on Gd-DTPA contrast enhanced MRI

ObjectivesThe purpose of this study was to develop and validate a radiomics nomogram for predicting thymidylate synthase (TYMS) status in hepatocellular carcinoma (HCC) by using Gd-DTPA contrast enhanced MRI.MethodsWe retrospectively enrolled 147 consecutive patients with surgically confirmed HCC and randomly allocated to training and validation set (7:3). The TYMS status was immunohistochemical determined and classified into low TYMS (positive cells ≤ 25%) and high TYMS (positive cells > 25%) groups. Radiomics features were extracted from the arterial phases and portal venous phase of Gd-DTPA contrast enhanced MRI. Least absolute shrinkage and selection operator (LASSO) were applied for generating the Rad score. Clinical data and MRI findings were assessed to build a clinical model. Rad score combined with clinical features was used to construct radiomics nomogram.ResultsA total of 2260 features were extracted and reduced to 7 features as the most important discriminators to build the Rad score. InAFP was identified as the only independent clinical factors for TYMS status. The radiomics nomogram showed good discrimination in training (AUC, 0.759; 95% CI 0.665–0.838) and validation set (AUC, 0.739; 95% CI 0.585–0.860), and showed better discrimination capability (P < 0.05) compared with clinical model in training (AUC, 0.656; 95% CI 0.555–0.746) and validation set (AUC, 0.622; 95% CI 0.463–0.764).ConclusionsThe radiomics nomogram shows favorable predictive efficacy for TYMS status in HCC, which might be helpful for the personalized treatment of HCC.

Targeting LINC01607 sensitizes hepatocellular carcinoma to Lenvatinib via suppressing mitophagy

Lenvatinib is a standard therapy option for advanced hepatocellular carcinoma (HCC), but resistance limits clinical benefits. In this study, we identified inhibition of ROS levels and reduced redox status in Lenvatinib-resistant HCC. Integrating RNA-seq with unbiased whole-genome CRISPR-Cas9 screen analysis indicated LINC01607 regulated the P62 to enhance drug resistance by affecting mitophagy and antioxidant pathways. Underlying mechanisms were investigated both in vitro and in vivo. We initially confirmed that LINC01607, as a competing endogenous RNA (ceRNA) competing with mirRNA-892b, triggered protective mitophagy by upregulating P62, which reduced ROS levels and promoted drug resistance. Furthermore, LINC01607 was proved to resist oxidative stress by regulating the P62-Nrf2 axis, which transcriptionally regulated the expression of LINC01607 to form a positive feedback loop. Finally, silencing LINC01607 combined with Lenvatinib reversed resistance in animal and patient-derived organoid models. In conclusion, we proposed a novel mechanism of Lenvatinib resistance involving ROS homeostasis. This work contributed to understanding redox homeostasis-related drug resistance and provided new therapeutic targets and strategies for HCC patients.

Near-infrared imaging of hepatocellular carcinoma and its medicinal treatment with a γ-glutamyl transpeptidase-monitoring fluorescence probe

Herein, the Near-infrared imaging of hepatocellular carcinoma (HCC) and its medicinal treatment was achieved with a γ-glutamyl transpeptidase (GGT)-monitoring fluorescence probe KYZ-GGT which consisted of the typical recognition group γ-glutamyl and the structurally modified signal reporting group hemicyanine-thioxanthene. Compared with the recently reported probes, KYZ-GGT suggested practical and steady capability for monitoring the GGT level in the cellular, xenograft, induced as well as medicinal treatment HCC models. It realized the mitochondrial targeting intracellular imaging to reflect the GGT dynamics in the induction or medicinal treatment of HCC. In the xenograft and induced model mice with multiple factors, KYZ-GGT showed stable performance for visualizing the HCC status. In the medicinal treatment of the long-period-induced HCC model mice verified by the serum indexes and histopathological analysis, KYZ-GGT successfully imaged the medicinal treatment process of HCC with two marketed drugs (Sorafenib and Lenvatinib) respectively, with an applicative penetration depth. The information here was meaningful for investigating effective medicinal strategies for overcoming HCC.

Unawareness of hepatitis B infection and lack of surveillance are associated with severity of hepatocellular carcinoma.

Unawareness of hepatitis B virus (HBV) infection and lack of surveillance may serve as major barriers to HBV control and contributors to severe hepatocellular carcinoma (HCC) at presentation. This study evaluated the risk of HBV unawareness and its relationship with HCC severity. This retrospective study was conducted in a tertiary hospital in Taiwan. Patients with HBV-related HCC diagnosed from 2011 to 2021 were enrolled. The demographic, clinical, and HCC characteristics were collected and compared between patients with HBV unawareness and awareness with and without surveillance. Of 501 HBV-related HCC patients enrolled, 105 (21%) patients were unaware of HBV infection at the time of HCC diagnosis. Patients with HBV unawareness were significantly younger and had poorer liver function than those with HBV awareness. Patients with HBV unawareness also had a significantly higher rate of detectable HBV DNA and an advanced stage of HCC. Ninety-one (23%) of the HBV-aware patients did not receive regular surveillance. Patients with HBV unawareness and awareness without surveillance shared similar clinical characteristics with more severe HCC status. Further regression analysis demonstrated that HBV awareness with periodic surveillance was associated with early stage HCC. Meanwhile, we observed that there was no change in the proportion of HBV awareness over the past 10 years. Patients with surveillance also had better HCC survival than patients without surveillance or unawareness. HBV unawareness and lack of regular surveillance correlated with advanced HCC at presentation. Efforts to improve HBV education, disease awareness, and HCC surveillance are needed.

P53 and VEGF are promising biomarkers for sorafenib efficacy in an experimental model of NASH-related HCC.

The efficacy of systemic therapy for hepatocellular carcinoma (HCC) related to non-alcoholic steatohepatitis (NASH) is poorly understood. In this study we evaluated the effects of sorafenib based on the expression of molecular markers related to major hepatocarcinogenesis pathways and angiogenesis in a NASH-related HCC model. Forty male rats were submitted to NASH-HCC induction through the combination of a high-fat and choline deficient diet and diethylnitrosamine (100mg/L) administration in the drinking water for 13 and 16weeks. After the induction period, the rats received daily gavage administration of saline solution (control) or Sorafenib (5mg/kg/day) for 3weeks. Thereafter, the animals were euthanized and samples from liver nodules were collected for histopathological analysis and immunohistochemical assessment of HEP-PAR-1, glutamine-synthetase, VEGF, survivin, β-catenin and p53. A semi-quantitative score was used for VEGF, survivin and β-catenin analysis. For p53, the percentage of positive cells was determined. Results were processed by Wilcoxon's test or Student's t-test. Both protocols efficiently induced HCC, most of them being moderately to poorly differentiated. Sorafenib-treated animals showed a decreased expression of VEGF and p53 in HCCs generated at 13weeks when compared to control animals (p = 0.03; p = 0.04, respectively). No significant difference in β-catenin and survivin were observed. There was a significant decrease in VEGF and p53 expression when comparing the two control groups (13 vs. 16weeks, p < 0.01). p53 and VEGF are promising biomarkers for assessment of efficacy of Sorafenib, whereas survivin and β-catenin were not found useful. Decreased immunohistochemical expression of p53 and VEGF in the 16week control group may indicate a different metabolic status of HCC.

ST6GALNAC4 promotes hepatocellular carcinogenesis by inducing abnormal glycosylation

Hepatocellular carcinoma (HCC) is one of the most lethal tumor types worldwide. Glycosylation has shown promise in the study of tumor mechanisms and treatment. The glycosylation status of HCC and the underlying molecular mechanisms are still not fully elucidated. Using bioinformatic analysis we obtained a more comprehensive characterization of glycosylation of HCC. Our analysis presented that high glycosylation levels might correlate with tumor progression and poor prognosis. Subsequent Experiments identified key molecular mechanisms for ST6GALNAC4 promoting malignant progression by inducing abnormal glycosylation. We confirmed the contribution of ST6GALNAC4 to proliferation, migration, and invasion in vitro and in vivo. Mechanistic studies revealed that ST6GALNAC4 may be induced abnormal TGFBR2 glycosylation, resulting in the higher protein levels of TGFBR2 and TGFbeta pathway increased activation. Our study also provided a further understand of immunosuppressive function of ST6GALNAC4 through T antigen-galectin3+ TAMs axis. This study has provided one such possibility that galectin3 inhibitors might be an acceptable treatment choice for HCC patients with high T antigen expression.

Characterization of the Clinical Significance and Immunological Landscapes of a Novel TMEMs Signature in Hepatocellular Carcinoma and the Contribution of TMEM201 to Hepatocarcinogenesis.

Aberrant transmembrane protein (TMEM) expression is implicated in tumor progression, but its functional role in hepatocellular carcinoma (HCC) is unclear. Thus, we aim to characterize the functional contributions of TMEM in HCC. In this study, four novel TMEM-family genes (TMEMs), TMEM106C, TMEM201, TMEM164, and TMEM45A, were screened to create a TMEMs signature. These candidate genes are distinguished between patients with varying survival statuses. High-risk HCC patients had a significantly worse prognosis and more advanced clinicopathological characteristics in both the training and validation groups. The GO and KEGG analyses unveiled that the TMEMs signature might play a crucial role in cell-cycle-relevant and immune-related pathways. We found that the high-risk patients had lower stromal scores and a more immunosuppressive tumor microenvironment with massive infiltration of macrophages and Treg cells, whereas the low-risk group had higher stromal scores and gamma delta T-cell infiltration. Moreover, the expression level of suppressive immune checkpoints increased as the TMEM-signature scores increased. Furthermore, the in vitro experiments validated TMEM201, one feature of the TMEMs signature, and facilitated HCC proliferation, survival, and migration. The TMEMs signature provided a more precise prognostic evaluation of HCC and reflected the immunological status of HCC. Of the TMEMs signature studied, TMEM201 was found to significantly promote HCC progression.

Real world impact of hepatocellular carcinoma stage and hepatic function on health-related quality of life.

e16215 Background: Health-Related Quality of Life (HRQoL) is an important prognostic indicator and clinical endpoint for patients with hepatocellular carcinoma (HCC). The relationship between cancer stage, liver function, performance status, and HRQoL in HCC in a real-world clinical setting is not well defined. Methods: A retrospective chart review was undertaken of consecutive patients with HCC treated at our institution's liver multidisciplinary clinic between February 2020 and August 2022. We examined the relationship between Barcelona Clinic Liver Cancer (BCLC) stage, Child Pugh (CP) score, and Eastern Cooperative Oncology Group (ECOG) performance status on HRQoL at diagnosis. HRQoL was assessed using the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire. Results: Fifty-one patients met our inclusion criteria. The median age was 69 and the mean FACT-Hep score was 130.3 ± 20.3. FACT-Hep total and subscales showed no significant association with BCLC stages A, B, and C (p =0.224), except in the Emotional Well Being (EWB) subscale (p =0.001). There was no impact of ECOG performance status on the FACT-Hep scores, except for the Functional Well Being (FWB) subscale (p=0.006). Patients with a CP B had significantly more impairment in FACT-Hep than patients with CP A, including FACT-Hep total score (118.5 ±27.3 versus 134.3 ±23.8; p =0.021) and subscales including the Physical Well Being (p =0.018), FWB (p =0.030), Hepatobiliary Cancer Subscale (p &lt;0.001), and FACT-Hep Trial Outcome Index score (p =0.003). Conclusions: Cancer stage poorly correlates with HRQoL at diagnosis in HCC patients. Impaired liver function reduces overall quality of life in HCC patients. Further large-scale prospective studies should be undertaken which incorporate validated HRQoL tools in the routine assessment of HCC patients. [Table: see text]