Liver Cancer In Adults Research Articles

Abstract 461: Pan-liver disease single cell-based deconvolution reveals γδ2 T cells as a marker in hepatocellular carcinoma development

Abstract Hepatocellular carcinoma (HCC) is the most common form of primary adult liver cancer and the fourth leading cause of cancer-related death worldwide. HCC incidence is highest most often in people with chronic liver diseases, yet the effect of cell composition on the progression of chronic liver diseases to HCC remains unknown. Using gene biomarkers of twenty cell-types identified from healthy liver scRNA-seq data, we estimated cell compositions of six chronic liver diseases and HCC based on their bulk RNA-seq samples. We observed a decrease in the enrichment of various health cells as the progression of liver diseases. Compared to a healthy state, liver fibrosis and HCC present higher enrichment of γδ2 T cells and lower enrichment of central venous liver sinusoidal endothelial cells (LSECs). High enrichment of γδ2 T cells was specifically observed in HCV and/or HBV positive HCC and advanced HCC. γδ2 T cell is one of the nine cell types that are associated with HCC prognosis. The analysis of multiple independent datasets confirmed that γδ2 T cells enrichment is more associated with poor prognosis in patients with lower Alpha-fetoprotein (AFP) level and HCV/HBV positive patients. Following pan-cancer analysis suggested enrichment of γδ2 T cells is associated with poor prognosis in kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, and low grade gliomas. In addition, this type of cells is also enriched in the blood samples of various chronic liver diseases and HCC, indicating the potential of being diagnostic markers. In summary, the integrative bioinformatics analysis identified γδ2 T cells as a marker for HCC progression. Citation Format: Rama Shankar, Jeremy Haskins, Shreya Paithankar, Bin Chen. Pan-liver disease single cell-based deconvolution reveals γδ2 T cells as a marker in hepatocellular carcinoma development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 461.

Knockdown of Atg7 suppresses Tumorigenesis in a murine model of liver cancer

Hepatocellular Carcinoma (HCC) is the most common type of primary liver cancer in adults and a leading cause of cancer-related deaths worldwide. Studies have shown that autophagy is significantly involved in carcinogenesis, in particular, driven by activated RAS signaling. Autophagy related 7 (Atg7) is a critical component for the formation of autophagosome and required for autophagy processes. We investigated the role of autophagy in RAS-driven tumorigenesis in the liver, via the knockdown of Atg7 in the model. Transposon vectors encoding short hairpin RNAs targeting Atg7 (Atg7 shRNA) were constructed. Inhibition of autophagy via Atg7 knockdown was tested in Hep3B cells cultured in nutrient-starved medium. Formation of autophagosome was suppressed in nutrient-starved Hep3B cells expressing Atg7 shRNA, demonstrating that it efficiently inhibited autophagy in HCC cells. Transposons encoding Atg7 shRNA were mixed with those expressing HRASG12V and p53 shRNA, and subsequently used for hydrodynamic injection to 5-week-old C57BL/6 mice. Tumorigenesis in livers induced by HRASG12V and p53 shRNA was significantly suppressed by Atg7 knockdown. The inhibition of autophagy led to a decreased proliferation of cancer cells, as determined by Ki-67 staining. Our data indicate that knockdown of Atg7 led to a significant decrease in tumorigenesis in a murine HCC model induced by activated RAS. Inhibition of autophagosome formation is expected to be a therapeutic option for liver cancer.

Anti-Cancer Effect of Moroccan Cobra Naja haje Venom and Its Fractions against Hepatocellular Carcinoma in 3D Cell Culture.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer in adults, the fifth most common malignancy worldwide and the third leading cause of cancer related death. An alternative to the surgical treatments and drugs, such as sorafenib, commonly used in medicine is necessary to overcome this public health problem. In this study, we determine the anticancer effect on HCC of Moroccan cobra Naja haje venom and its fraction obtained by gel filtration chromatography against Huh7.5 cancer cell line. Cells were grown together with WI38 human fibroblast cells, LX2 human hepatic stellate cell line, and human endothelial cells (HUVEC) in MCTS (multi-cellular tumor spheroids) models. The hepatotoxicity of venom and its fractions were also evaluated using the normal hepatocytes cell line (Fa2N-4 cells). Our results showed that an anti HCC activity of Moroccan cobra Naja haje venom and, more specifically, the F7 fraction of gel filtration chromatography exhibited the greatest anti-hepatocellular carcinoma effect by decreasing the size of MCTS. This effect is associated with a low toxicity against normal hepatocytes. These results strongly suggest that the F7 fraction of Moroccan cobra Naja haje venom obtained by gel filtration chromatography possesses the ability to inhibit cancer cells proliferation. More research is needed to identify the specific molecule(s) responsible for the anticancer effect and investigate their mechanism of action.

Comparison of various approaches to combine logistic regression with genetic algorithms in survival prediction of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common liver cancer in adults. Many different factors make it difficult to diagnose in humans.. In this paper, a novel diagnostics approach based on machine learning techniques is presented. Logistic regression is one of the most classic machine learning models used to solve the problem of binary classification. In typical implementations, logistic regression coefficients are optimized using iterative methods. Additionally, parameters such as solver, C - a regularization parameter or the number of iterations of the algorithm operation should be selected. In our research, we propose a combination of logistic regression with genetic algorithms. We present three experiments showing the fusion of those methods. In the first experiment, we genetically select the logistic regression parameters, while the second experiment extends this approach by including a genetic selection of features. The third experiment presents a novel approach to train the logistic regression model - the genetic selection of coefficients (weights). Our models are tested for the survival prediction of hepatocellular carcinoma based on patient data collected at Coimbra's Hospital and Universitary Center (CHUC), Portugal. The model we proposed achieved a classification accuracy of 94.55% and an f1-score of 93.56%. Our algorithm shows that machine learning techniques optimized by the proposed concept can bring a new and accurate approach in HCC diagnosis with high accuracy.

Deep Learning-Based Hepatocellular Carcinoma Histopathology Image Classification: Accuracy Versus Training Dataset Size

Globally, liver cancer causes more than 700,000 deaths each year and is the second-leading cause of death from cancer. Hepatocellular carcinoma (HCC) is the most common type of liver cancer in adults and accounts for most deaths in cirrhosis patients. Patients with early-stage liver cancer can be treated by surgical intervention with a good prognosis; thus, early diagnosis, as confirmed by liver pathology examination, is necessary to combat HCC. Conventional manual pathology examination requires considerable time and labor, even with established expertise. It is widely accepted that intelligent classifiers may prove effective in the diagnosis process. In this study, we used a GoogLeNet (Inception-V1)-based binary classifier to classify HCC histopathology images. The classifier achieved 91.37% (±2.49) accuracy, 92.16% (±4.93) sensitivity, and 90.57% (±2.54) specificity in HCC classification. Although the classification accuracy of deep learning is reported to be positively correlated with the amount of training data, it is often uncertain how much training data are required for deep learning to achieve satisfactory performance in clinical diagnosis. Moreover, deep learning methods require annotated data to generate efficient models. However, annotated data are a relatively scarce resource and can be expensive to obtain. Hence, the relationship between classification accuracy and the number of liver histopathology images for training was investigated. An inverse power law function-based estimation model is proposed to evaluate the minimum number of annotated training images required for a desired diagnostic accuracy.

Abstract PO-054: Hepatitis B and C screening and knowledge of liver cancer in underserved Chinese American adults in New York City: A community-based assessment

Abstract Background Of all liver cancer cases detected in the United States, approximately 70% are caused by hepatitis B and C virus (HBV and HCV). Asian Americans (AAs) are disproportionally affected by liver cancer, with a mortality rate 60% higher than that of non-Hispanic White. In recent years the incidence rate of liver cancer in New York City has been 35% higher than the national average. Methods In New York City, we collaboratively developed and conducted a liver cancer prevention education with community-based organizations to increase awareness of liver cancer prevention and screening. Assessment data was collected from Asian American community members who participated in our educational workshops. Preliminary findings from 53 participants' knowledge on HBV, HCV, and liver cancer prior to the intervention, will be reported in this presentation. Chi-square and t-test were used to conduct data analysis. Results Almost half of the participants reported hearing about HBV (48.1%) and HCV (60.4%) from their medical team, and even fewer of them ever received HBV (37.7%) and HCV (9.4%) testing. Participants were knowledgeable on HBV/HCV transmission (scored 7.9 out of 10), they lack the knowledge on liver cancer risk factors (scored 1.9 out of 5). Those who were covered with health insurance were more knowledgeable on identifying risk factors of liver cancer than those uncovered (1.94 vs. 1.00, p<0.001). Conclusions Our findings show that there is a pressing need for educational intervention, especially in New York City, to promote liver cancer interventions among at-risk Asian Americans. Citation Format: Wenyue Lu, Kerry Traub, Safa Ibrahim, Elizabeth Yi, Ada Wong, Evelyn Gonzalez, Lin Zhu, Marilyn A. Fraser, Yin Tan, Olorunseun Ogunwobi, Grace X. Ma, Ming-Chin Yeh. Hepatitis B and C screening and knowledge of liver cancer in underserved Chinese American adults in New York City: A community-based assessment [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-054.

Human aflatoxin exposure in Uganda: Estimates from a subset of the 2011 Uganda AIDS indicator survey (UAIS)

ABSTRACT Aflatoxins are carcinogenic mycotoxins that contaminate a variety of crops worldwide. Acute exposure can cause liver failure, and chronic exposure can lead to stunting in children and liver cancer in adults. We estimated aflatoxin exposure across Uganda by measuring a serum biomarker of aflatoxin exposure in a subsample from the 2011 Uganda AIDS Indicator Survey, a nationally representative survey of HIV prevalence, and examined its association with geographic, demographic, and socioeconomic variables. We analysed a subsample of 985 serum specimens selected among HIV-negative participants from 10 survey-defined geographic regions for serum aflatoxin B1-lysine (AFB1-lys) by use of isotope dilution LC-MS/MS and calculated results normalised to serum albumin. We used statistical techniques for censored data to estimate geometric means (GMs), standard deviations, and percentiles. We detected serum AFB1-lys in 71.7% of specimens (LOD = 0.5 pg/mg albumin). Unadjusted GM AFB1-lys (pg/mg albumin) was 1.33 (95% CI: 1.21–1.47). Serum AFB1-lys was higher in males (GM: 1.57; 95% CI: 1.38–1.80) vs. females (GM: 1.12; 95% CI: 0.97–1.30) (P = .0019), and higher in persons residing in urban settings (GM: 2.83; 95% CI: 2.37–3.37) vs. rural (GM: 1.10; 95% CI: 0.99–1.23) (P < .0001). When we used a multivariable censored regression model to assess confounding and interactions among variables we found that survey region, gender, age, occupation, distance to marketplace, and number of meals per day were statistically significant predictors of aflatoxin exposure. While not nationally representative, our findings provide an improved understanding of the widespread burden of aflatoxin exposure throughout Uganda and identify key geographic, demographic, and socioeconomic factors that may modulate aflatoxin exposure risk.

HP1s modulate the S-Adenosyl Methionine synthesis pathway in liver cancer cells.

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer in adults. Among the altered pathways leading to HCC, an increasing role is attributed to abnormal epigenetic regulation. Members of the Heterochromatin Protein (HP1) 1 family are key players in chromatin organisation, acting as docking sites for chromatin modifiers. Here, we inactivated HP1α in HepG2 human liver carcinoma cells and showed that HP1α participated in cell proliferation. HP1α-depleted cells have a global decrease in DNA methylation and consequently a perturbed chromatin organisation, as exemplified by the reactivation of transcription at centromeric and pericentromeric regions, eventhough the protein levels of chromatin writers depositing methylation marks, such as EZH2, SETDB1, SUV39H1, G9A and DNMT3A remained unaltered. This decrease was attributed mainly to a low S-Adenosyl Methionine (SAM) level, a cofactor involved in methylation processes. Furthermore, we showed that this decrease was due to a modification in the Methionine adenosyl transferase 2A RNA (MAT2A) level, which modifies the ratio of MAT1A/MAT2A, two enzymes that generate SAM. Importantly, HP1α reintroduction into HP1α-depleted cells restored the MAT2A protein to its initial level. Finally, we demonstrated that this transcriptional deregulation of MAT2A in HP1α-depleted cells relied on a lack of recruitment of HP1β and HP1γ to MAT2A promoter where an improper non-CpG methylation site was promoted in the vicinity of the transcription start site where HP1β and HP1γ bound. Altogether, these results highlight an unanticipated link between HP1 and the SAM synthesis pathway, and emphasise emerging functions of HP1s as sensors of some aspects of liver cell metabolism.

Harnessing big 'omics' data and AI for drug discovery in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common form of primary adult liver cancer. After nearly a decade with sorafenib as the only approved treatment, multiple new agentshave demonstrated efficacy in clinical trials, including the targeted therapies regorafenib, lenvatinib and cabozantinib, the anti-angiogenic antibody ramucirumab, and the immune checkpoint inhibitors nivolumab and pembrolizumab. Although these agents offer new promise to patients with HCC, the optimal choice and sequence of therapies remains unknown and without established biomarkers, and many patients do not respond to treatment. The advances and the decreasing costs of molecular measurement technologies enable profiling of HCC molecular features (such as genome, transcriptome, proteome and metabolome) at different levels, including bulk tissues, animal models and single cells. The release of such data sets to the public enhances the ability to search for information from these legacy studies and provides theopportunity to leverage them to understand HCC mechanisms, rationally develop new therapeutics and identify candidate biomarkers of treatment response. Here, we provide a comprehensive review of public data sets related to HCC and discuss how emerging artificial intelligence methods can be applied to identify new targets and drugs as well as to guide therapeutic choices for improved HCC treatment.

Aberrant AFP expression characterizes a subset of hepatocellular carcinoma with distinct gene expression patterns and inferior prognosis.

Background Serum tumor markers are ubiquitously used in the clinic for cancer screening. However, the mechanisms accounting for the elevated levels of the serum tumor markers remain to be explored.Methods We performed a pan-cancer analysis of serum alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) and prostate-specific antigen (PSA). The relation between concentration of serum tumor markers and the expression of their coding genes was assessed. Then the expression of AFP and its genomic background in hepatocellular carcinoma (liver cancer) was studied.Results High expression of AFP mRNA was found mainly in liver cancer. In gastric cancer, breast cancer and lung cancer, high AFP mRNA expression was also discovered occasionally. In liver cancer patients, serum AFP levels correlated significantly with AFP mRNA expression in cancer tissues (r = 0.72, p = 1.6e-45). Whole transcriptome analysis revealed that serum AFP levels clearly separated liver cancer into two classes with distinct expression profiles according to PCA analysis. Gene co-expression analysis revealed that AFP expression was connected to a module enriched with genes accounting for cell cycle and cell proliferation regulation. In addition, high AFP expression was associated with the molecular classification of liver cancer, including iCluster (Chi-square: 16.86, P = 0.0002). Methylation analysis revealed de-methylation of AFP promoter occurred in some liver cancer tissues, which was significantly related to AFP mRNA expression. Survival analysis indicated high serum AFP levels was prognostic of poorer survival of the liver cancer patients (Log-rank test: p = 0.046). This was confirmed by an independent dataset in which liver cancer patients with high serum AFP also had poorer survival (Log-rank test: p = 0.024).Conclusion High expression of AFP defined a subtype of liver cancer with distinct gene expression profiles and clinical features. De-methylation of cytosine from CpG di-nucleotides in AFP promoter may be the cause of AFP re-expression in adult human liver cancer tissue.

Long non-coding RNA MALAT1 promotes angiogenesis and immunosuppressive properties of HCC cells by sponging miR-140.

Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer in adults. Previous studies in our laboratory found that long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was upregulated in HCC cells, which could affect the metastasis and invasion of HCC. However, the underlying mechanism remains unknown. Herein, we studied the interaction between MALAT1 and miR-140 on the regulation of angiogenesis and immunosuppressive properties. We revealed that the expression of MALAT1 and VEGF-A was significantly increased in HCC cells. Knockdown of MALAT1 in HCC cells suppressed the production of VEGF-A, impaired the angiogenesis of HUVECs, and facilitated the polarization of macrophage toward the M1 subset. Mechanistically, the interaction between MALAT1 and miR-140 or between miR-140 and VEGF-A was confirmed by multiple assays. Besides, a negative correlation between MALAT1 and miR-140 was found in HCC tissues. Furthermore, miR-140 inhibition significantly increased VEGF-A expression, promoted angiogenesis of HUVECs, and redirected the polarization of macrophages toward the M2 subset. In addition, in vivo studies also verified the regulatory network of the MALAT1/miR-140 axis on VEGF-A in HCC progression. In summary, this study revealed the mechanism that MALAT1 worked as a putative HCC promotor via inhibiting miR-140. Therefore, targeting MALAT1 or miR-140 might alleviate the progression of HCC in the future.

Alternative hepatitis B vaccine strategies in healthy non-responders to a first standard vaccination scheme

Hepatitis B virus (HBV) infection is a major public health problem with an estimated 257 million people with chronic HBV infection and around 650 000 annual deaths due to long-term HBV-related liver disease (cirrhosis and hepatocellular carcinoma). 1 Whitford K Liu B Micallef J et al. Long-term impact of infant immunization on hepatitis B prevalence: a systematic review and meta-analysis. Bull World Health Organ. 2018; 96: 484-497 Crossref PubMed Scopus (25) Google Scholar Vaccination represents the cornerstone of public health measures to eradicate HBV. The implementation of effective infant vaccination programmes in many countries has resulted in a significant decrease in the prevalence of HBV infection and in the incidence of liver cancer in children and young adults. 1 Whitford K Liu B Micallef J et al. Long-term impact of infant immunization on hepatitis B prevalence: a systematic review and meta-analysis. Bull World Health Organ. 2018; 96: 484-497 Crossref PubMed Scopus (25) Google Scholar , 2 Schweitzer A Horn J Mikolajczyk RT Krause G Ott JJ Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet. 2015; 386: 1546-1555 Summary Full Text Full Text PDF PubMed Scopus (1812) Google Scholar , 3 Wiesen E Diorditsa S Li X Progress towards hepatitis B prevention through vaccination in the Western Pacific, 1990–2014. Vaccine. 2016; 34: 2855-2862 Crossref PubMed Scopus (41) Google Scholar Serological response to three alternative series of hepatitis B revaccination (Fendrix, Twinrix, and HBVaxPro-40) in healthy non-responders: a multicentre, open-label, randomised, controlled, superiority trialRevaccinating healthy non-responders with Fendrix or HBVaxPro-40 resulted in significantly higher proportions of responders and therefore indication for these vaccines should be expanded to enable revaccination of non-responders. Full-Text PDF

Animal Models of Hepatocellular Carcinoma: The Role of Immune System and Tumor Microenvironment.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer in adults and has one of the highest mortality rates of solid cancers. Ninety percent of HCCs are associated with liver fibrosis or cirrhosis developed from chronic liver injuries. The immune system of the liver contributes to the severity of the necrotic-inflammatory tissue damage, the establishment of fibrosis and cirrhosis, and the disease progression towards HCC. Immunotherapies have emerged as an exciting strategy for HCC treatment, but their effect is limited, and an extensive translation research is urgently needed to enhance anti-tumor efficacy and clinical success. Establishing HCC animal models that are analogous to human disease settings, i.e., mimicking the tumor microenvironment of HCC, is extremely challenging. Hence, this review discusses different animal models of HCC by summarizing their advantages and their limits with a specific focus on the role of the immune system and tumor microenvironment.

Parkin facilitates proteasome inhibitor-induced apoptosis via suppression of NF-\u03baB activity in hepatocellular carcinoma

The ubiquitin–proteasome system (UPS) is a tight homeostatic control mechanism of intracellular protein degradation and turnover involved in many human diseases. Proteasome inhibitors were initially developed as anticancer agents with potential benefits in the suppression of tumor growth. However, clinical trials of patients with solid tumors fail to demonstrate the same efficacy of these proteasome inhibitors. Here, we show that Parkin, an E3 ubiquitin ligase, is implicated in tumorigenesis and therapy resistance of hepatocellular carcinoma (HCC), the most common type of primary liver cancer in adults. Lower Parkin expression correlates with poor survival in patients with HCC. Ectopic Parkin expression enhances proteasome inhibitor-induced apoptosis and tumor suppression in HCC cells in vitro and in vivo. In contrast, knockdown of Parkin expression promotes apoptosis resistance and tumor growth. Mechanistically, Parkin promotes TNF receptor-associated factor (TRAF) 2 and TRAF6 degradation and thus facilitates nuclear factor-kappa-B (NF-κB) inhibition, which finally results in apoptosis. These findings reveal a direct molecular link between Parkin and protein degradation in the control of the NF-κB pathway and may provide a novel UPS-dependent strategy for the treatment of HCC by induction of apoptosis.

Gene Ontology and Expression Studies of Strigolactone Analogues on a Hepatocellular Carcinoma Cell Line.

Human hepatocellular carcinoma (HCC) is the most common and recurrent type of primary adult liver cancer without any effective therapy. Plant-derived compounds acting as anticancer agents can induce apoptosis by targeting several signaling pathways. Strigolactone (SL) is a novel class of phytohormone, whose analogues have been reported to possess anticancer properties on a panel of human cancer cell lines through inducing cell cycle arrest, destabilizing microtubular integrity, reducing damaged in the DNA repair machinery, and inducing apoptosis. In our previous study, we reported that a novel SL analogue, TIT3, reduces HepG2 cell proliferation, inhibits cell migration, and induces apoptosis. To decipher the mechanisms of TIT3-induced anticancer activity in HepG2, we performed RNA sequencing and the differential expression of genes was analyzed using different tools. RNA-Seq data showed that the genes responsible for microtubule organization such as TUBB, BUB1B, TUBG2, TUBGCP6, TPX2, and MAP7 were significantly downregulated. Several epigenetic modulators such as UHRF1, HDAC7, and DNMT1 were also considerably downregulated, and this effect was associated with significant upregulation of various proapoptotic genes including CASP3, TNF-α, CASP7, and CDKN1A (p21). Likewise, damaged DNA repair genes such as RAD51, RAD52, and DDB2 were also significantly downregulated. This study indicates that TIT3-induced antiproliferative and proapoptotic activities on HCC cells could involve several signaling pathways. Our results suggest that TIT3 might be a promising drug to treat HCC.

Triple amplified ultrasensitive electrochemical immunosensor for alpha fetoprotein detection based on MoS2@Cu2O-Au nanoparticles

Recently, alpha fetoprotein (AFP), a tumour marker to identify adult primary liver cancer, has attracted increasingly widespread attention. In this work, an ultrasensitive sandwich-type electrochemical biosensor was fabricated for AFP detection. Electrodeposited gold nanoparticles (D-Au NPs) modified on glassy carbon electrodes (GCE) were used as antibody carriers and sensing platforms. Furthermore, a molybdenum disulfide @ cuprous oxide hybrid (MoS2@Cu2O) was prepared to combine gold nanoparticles (Au NPs) as a strategy for achieving signal amplification. The experimental results revealed that molybdenum disulfide @ cuprous oxide-gold nanoparticles (MoS2@Cu2O-Au) showed superb tri-amplification electrochemical signals when catalyzing hydrogen peroxide (H2O2) reduction. This method was demonstrated as a novel tool for the highly reliable separation and quantification of AFP. Under the most suitable experimental conditions, the proposed method exhibits a linear range from 0.1 pg/mL to 50 ng/mL and a low detection limit of 0.037 pg/mL (S/N = 3). The ultrasensitive electrochemical immunosensor has been tested for human serum, and satisfactory recoveries were obtained, indicating that the proposed method is promising for practical applications in the clinical diagnosis of AFP detection.

Thymoquinone exerts anti-tumor activities on human hepatocellular carcinoma cells: role of angiogenesis-related genes VCAN, Grb2 and EZH2

Human hepatocellular carcinoma (HCC) is the most prevalent and recurrent type of primary adult liver cancer without any effective therapy. Thus, there is an increase demands for finding new drugs and treatment strategies with selective and potent effects towards HCC. Plant-derived compounds acting as anti-cancer agents can induce apoptosis through targeting several signaling pathways. Thymoquinone (TQ), the major biologically active compound of the black seed oil (Nigella sativa) has demonstrated inhibitory activities on various cancers by targeting several pathways. In the present study, we have evaluated the molecular mechanisms that underlie the anti-proliferative, anti-metastatic, and pro-apoptotic activities exerted by TQ on liver cancer cell lineHepG2, a well-documented HCC in vitro model. Cell proliferation was determined by WST-1 assay, apoptosis rate was assessed by flow cytometry using annexin-V/7AAD staining, wound healing assay to investigate the metastasis, and the expression of target genes was assessed by Real-time RT–PCR analysis. We found that TQ significantly reduced HepG2 cell viability and induced apoptosis in a dose-dependent manner. Migration of HepG2 cells was suppressed in response to TQ. Moreover, TQ decreased the expression of several angiogenesis-related genes including versican (VCAN), growth factor receptor-bound protein 2 (Grb2), and the histone methyltransferase for lysine 27 of histone 3 (EZH2). The findings suggest that TQ exerts inhibitory effects on HCC most likely through targeting key genes involved in the invasiveness and

Characterization of Lipid and Lipid Droplet Metabolism in Human HCC.

Human hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and the most common cause of death in people with cirrhosis. While previous metabolic studies of HCC have mainly focused on the glucose metabolism (Warburg effect), less attention has been paid to tumor-specific features of the lipid metabolism. Here, we applied a computational approach to analyze major pathways of fatty acid utilization in individual HCC. To this end, we used protein intensity profiles of eleven human HCCs to parameterize tumor-specific kinetic models of cellular lipid metabolism including formation, enlargement, and degradation of lipid droplets (LDs). Our analysis reveals significant inter-tumor differences in the lipid metabolism. The majority of HCCs show a reduced uptake of fatty acids and decreased rate of β-oxidation, however, some HCCs display a completely different metabolic phenotype characterized by high rates of β-oxidation. Despite reduced fatty acid uptake in the majority of HCCs, the content of triacylglycerol is significantly enlarged compared to the tumor-adjacent tissue. This is due to tumor-specific expression profiles of regulatory proteins decorating the surface of LDs and controlling their turnover. Our simulations suggest that HCCs characterized by a very high content of triglycerides comprise regulatory peculiarities that render them susceptible to selective drug targeting without affecting healthy tissue.

Central adiposity in relation to risk of liver cancer in Chinese adults: A prospective study of 0.5 million people.

Central adiposity is associated with liver cancer risk beyond general adiposity in Western populations. However, there is little prospective evidence in East Asian populations who are more likely to have central adiposity at given BMI levels. The prospective China Kadoorie Biobank recruited 512,713 adults aged 30–79 years from 10 diverse areas. During 10 years follow‐up, 2,847 incident cases of liver cancer were identified. Cox regression was used to estimate adjusted hazard ratios (HR) for liver cancer associated with central adiposity, excluding individuals with cancers and liver diseases at baseline and the first 5 years of follow‐up (1,049 incident liver cancer cases). Overall, mean waist circumference (WC) was 82.2 (SD 9.8) cm in men and 79.1 (9.5) cm in women. Central adiposity showed positive associations with liver cancer risk. Associations were strongest for WC and waist‐to‐hip ratio (WHR), with adjusted HRs per 1‐SD of 1.09 (95%CI 1.01–1.18) and 1.12 (1.02–1.23), respectively. The positive associations became stronger when additionally adjusting for BMI (1.26 [1.09–1.46] and 1.14 [1.02–1.28]). The positive association of central obesity (WC ≥90 cm in men and ≥ 80 cm in women) with liver cancer increased progressively with the number of other presenting metabolic risk factors (physical inactivity, diabetes, and hypertension), with HRs of 1.07 (0.90–1.28), 1.17 (1.00–1.38), and 1.91 (1.40–2.59) in those with one, two, and three factors (p for trend 0.006). In this relatively lean Chinese population, there were positive associations of central adiposity with risk of liver cancer, with WHR and WC showing the strongest associations.

Hepatocellular Carcinoma and Associated Clinical Features in Latino and Caucasian Patients from a Single Center

Introduction and aimHepatocellular carcinoma (HCC) is the most common type of liver cancer in adults and has seen a rapid increase in incidence in the United States. Racial and ethnic differences in HCC incidence have been observed, with Latinos showing the greatest increase over the past four decades, highlighting a concerning health disparity. The goal of the present study was to compare the clinical features at the time of diagnosis of HCC in Latino and Caucasian patients. Material and methodsWe retrospectively screened a total of 556 charts of Latino and Caucasian patients with HCC. ResultsThe mean age of HCC diagnosis was not significantly different between Latinos and Caucasians, but Latinos presented with higher body mass index (BMI). Rates of hypertension, diabetes, and hyperlipidemia were similar in the two groups. The most common etiology of liver disease was alcohol drinking in Latinos, and chronic hepatitis C in Caucasian patients. Non-Alcoholic Steatohepatitis (NASH) was the associated diagnosis in 8.6% of Latinos and 4.7% of Caucasians. Interestingly, alpha-fetoprotein (AFP) levels at time of diagnosis were higher in Latino patients compared to Caucasians, but this difference was evident only in male patients. Multifocal HCC was slightly more frequent in Latinos, but the two groups had similar cancerous vascular invasion. Latino patients also presented with higher rates of both ascites and hepatic encephalopathy. ConclusionLatino and Caucasian patients with HCC present with a different profile of etiologies, but cancer features appear to be more severe in Latinos.