DNA methylation alterations of ADCY5, MICAL2, and PLEKHG2 during the developmental stage of cryptogenic hepatocellular carcinoma.

AIM: The aim of this study was to clarify the significance of DNA methylation alterations of cryptogenic hepatocellular carcinomas (HCCs). METHODS: Using the Infinium assay, we performed genome-wide DNA methylation analysis of 250 liver tissue samples, including noncancerous liver tissue (U-N) and corresponding cancerous tissue (U-T) from patients with cryptogenic HCC without a history of excessive alcohol use and hepatitis virus infection, and whose U-N samples showed no remarkable histological features (no microscopic evidence of simple steatosis, any form of hepatitis including nonalcoholic steatohepatitis, or liver cirrhosis). RESULTS: We identified 3272 probes that showed significant differences of DNA methylation levels between U-N and normal liver tissue samples from patients without HCC, indicating that a distinct DNA methylation profile had already been established at the precancerous U-N stage. U-Ns have a DNA methylation profile differing from that of noncancerous liver tissue of patients with nonalcoholic steatohepatitis-related, viral hepatitis-related, and alcoholic liver disease-related HCCs. Such DNA methylation alterations in U-Ns were inherited by U-Ts. The U-Ns showed DNA methylation alteration of ADCY5, resulting in alteration of its mRNA expression, whereas noncancerous liver tissue of patients with nonalcoholic steatohepatitis-, viral hepatitis-, or alcoholic liver disease-related HCCs did not. DNA methylation levels of MICAL2 and PLEKHG2 in U-Ts were correlated with larger tumor diameter and portal vein involvement, respectively. CONCLUSIONS: U-N-specific DNA hypermethylation of ADCY5 may have significance, even from the precancerous stage in liver showing no remarkable histological features. DNA hypomethylation of MICAL2 and PLEKHG2 may determine the clinicopathological features of cryptogenic HCC.

Appearance of sex-determining region Y-box 9 (SOX9)- and glutathione S-transferase placental form (GST-P)-positive hepatocytes as possible carcinogenic events in the early stage of furan-induced hepatocarcinogenesis.

Furan, the basic skeleton of various flavoring agents, induces cholangiocellular tumors with higher incidences in the caudate lobe and hepatocellular tumors without the lobe specificity in rats, but the mechanism is unclear. We investigated the lobe distribution of possible carcinogenic events. Furan caused proliferation/infiltration of oval and inflammatory cells prominently in the caudate lobe as early as 4 weeks and cholangiofibrosis in this lobe at 8 weeks. In vivo mutagenicity assays using DNA extracted from the caudate or left lateral lobe of male gpt delta rats, the reporter gene-transgenic rats, treated with 8 mg/kg furan for 4 or 8 weeks showed negative outcomes. The distribution of glutathione S-transferase placental form (GST-P)-positive or sex-determining region Y-box 9 (SOX9)-positive hepatocytes was examined. Significant increases in the number of GST-P-positive hepatocytes were observed in all lobes of furan-treated rats at 8 weeks. By contrast, SOX9-positive hepatocytes, liver injury-inducible progenitor cells, were also found in all lobes of treated rats, the incidences of which were by far the highest in the caudate lobe. In addition, some of these hepatocytes also co-expressed delta like 1 homolog (DLK1), a hepatoblast marker, particularly in areas with a predominant presence of inflammatory cells. Overall, furan induced liver injury, leading to the appearance of SOX9-positive hepatocytes, some of which were subjected to dedifferentiation in the inflammatory microenvironment of a cholangiocarcinoma-prone lobe. Thus, the appearance of SOX9-positive hepatocytes together with GST-P-positive hepatocytes could be initial events in furan-induced hepatocarcinogenesis via non-genotoxic mechanisms.

Fibrosis and Hepatocarcinogenesis: Role of Gene-Environment Interactions in Liver Disease Progression.

The liver is a complex organ that performs vital functions in the body. Despite its extraordinary regenerative capacity compared to other organs, exposure to chemical, infectious, metabolic and immunologic insults and toxins renders the liver vulnerable to inflammation, degeneration and fibrosis. Abnormal wound healing response mediated by aberrant signaling pathways causes chronic activation of hepatic stellate cells (HSCs) and excessive accumulation of extracellular matrix (ECM), leading to hepatic fibrosis and cirrhosis. Fibrosis plays a key role in liver carcinogenesis. Once thought to be irreversible, recent clinical studies show that hepatic fibrosis can be reversed, even in the advanced stage. Experimental evidence shows that removal of the insult or injury can inactivate HSCs and reduce the inflammatory response, eventually leading to activation of fibrolysis and degradation of ECM. Thus, it is critical to understand the role of gene-environment interactions in the context of liver fibrosis progression and regression in order to identify specific therapeutic targets for optimized treatment to induce fibrosis regression, prevent HCC development and, ultimately, improve the clinical outcome.

hnRNPA2B1 promotes the occurrence and progression of hepatocellular carcinoma by downregulating PCK1 mRNA via a m6A RNA methylation manner.

BACKGROUND: N6-methyladenosine (m6A) is the most prevalent RNA modification. Although hnRNPA2B1, as a reader of m6A modification, has been reported to promote tumorigenesis in a few types of tumors, its role in hepatocellular carcinoma (HCC) and the underlying molecular mechanism remains unclear. METHODS: Multiple public databases were used to analyze the expression of hnRNPA2B1 in HCC and its correlation with survival prognosis. We employed a CRISPR-Cas9 sgRNA editing strategy to knockout hnRNPA2B1 expression in HCC cells. The biological function of hnRNPA2B1 in vitro in HCC cells was measured by CCK8, colony formation, migration, and invasion assay. The tumorigenic function of hnRNPA2B1 in vivo was determined by a subcutaneous tumor formation experiment and a HCC mouse model via tail injection of several plasmids into the mouse within 5s-7s. RNA binding protein immunoprecipitation (RIP) experiment using hnRNPA2B1 was performed to test the target genes of hnRNPA2B1 and methylated RNA immunoprecipitation (MeRIP) assay was performed to explore the m6A methylated mRNA of target genes. RESULTS: hnRNPA2B1 highly expressed in HCC tissues, correlated with high grades and poor prognosis. Its knockout reduced HCC cell proliferation, migration, and invasion in vitro, while overexpression promoted these processes. hnRNPA2B1-knockout cells inhibited tumor formation in graft experiments. In HCC mice, endogenous knockout attenuated hepatocarcinogenesis. RNA-seq showed downregulated gluconeogenesis with high hnRNPA2B1 expression. hnRNPA2B1 negatively correlated with PCK1, a key enzyme. RIP assay revealed hnRNPA2B1 binding to PCK1 mRNA. hnRNPA2B1 knockout increased m6A-methylation of PCK1 mRNA. Interestingly, PCK1 knockout partially counteracted tumor inhibition by hnRNPA2B1 knockout in mice. CONCLUSION: Our study indicated that hnRNPA2B1 is highly expressed in HCC and correlated with a poor prognosis. hnRNPA2B1 promotes the tumorigenesis and progression of HCC both in vitro and in vivo. Moreover, hnRNPA2B1 downregulates the expression of PCK1 mRNA via a m6A methylation manner. More importantly, the ability of hnRNPA2B1 to induce tumorigenesis and progression in HCC is dependent on its ability to decrease the expression of PCK1. Therefore, this study suggested that hnRNPA2B1 might be a diagnostic marker of poor prognosis of HCC and a potential therapeutic target for HCC patients.

mTOR-dependent loss of PON1 secretion and antiphospholipid autoantibody production underlie autoimmunity-mediated cirrhosis in transaldolase deficiency.

Transaldolase deficiency predisposes to chronic liver disease progressing from cirrhosis to hepatocellular carcinoma (HCC). Transition from cirrhosis to hepatocarcinogenesis depends on mitochondrial oxidative stress, as controlled by cytosolic aldose metabolism through the pentose phosphate pathway (PPP). Progression to HCC is critically dependent on NADPH depletion and polyol buildup by aldose reductase (AR), while this enzyme protects from carbon trapping in the PPP and growth restriction in TAL deficiency. Although AR inactivation blocked susceptibility to hepatocarcinogenesis, it enhanced growth restriction, carbon trapping in the non-oxidative branch of the PPP and failed to reverse the depletion of glucose 6-phosphate (G6P) and liver cirrhosis. Here, we show that inactivation of the TAL-AR axis results in metabolic stress characterized by reduced mitophagy, enhanced overall autophagy, activation of the mechanistic target of rapamycin (mTOR), diminished glycosylation and secretion of paraoxonase 1 (PON1), production of antiphospholipid autoantibodies (aPL), loss of CD161+ NK cells, and expansion of CD38+ Ito cells, which are responsive to treatment with rapamycin in vivo. The present study thus identifies glycosylation and secretion of PON1 and aPL production as mTOR-dependent regulatory checkpoints of autoimmunity underlying liver cirrhosis in TAL deficiency.

Nuclear translocation of YAP drives BMI-associated hepatocarcinogenesis in hepatitis B virus infection.

BACKGROUND AND AIMS: Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC) development and progression. The aim of this study was to mechanistically investigate the involvement of Hippo signalling in HBV surface antigen (HBsAg)-dependent neoplastic transformation. METHODS: Liver tissue and hepatocytes from HBsAg-transgenic mice were examined for the Hippo cascade and proliferative events. Functional experiments in mouse hepatoma cells included knockdown, overexpression, luciferase reporter assays and chromatin immunoprecipitation. Results were validated in HBV-related HCC biopsies. RESULTS: Hepatic expression signatures in HBsAg-transgenic mice correlated with YAP responses, cell cycle control, DNA damage and spindle events. Polyploidy and aneuploidy occurred in HBsAg-transgenic hepatocytes. Suppression and inactivation of MST1/2 led to the loss of YAP phosphorylation and the induction of BMI1 expression in vivo and in vitro. Increased BMI1 directly mediated cell proliferation associated with decreased level of p16INK4a , p19ARF , p53 and Caspase 3 as well as increased Cyclin D1 and γ-H2AX expression. Chromatin immunoprecipitation and the analysis of mutated binding sites in dual-luciferase reporter assays confirmed that the YAP/TEAD4 transcription factor complex bound and activated the Bmi1 promoter. In chronic hepatitis B patients, paired liver biopsies of non-tumour and tumour tissue indicated a correlation between YAP expression and the abundance of BMI1. In a proof-of-concept, treatment of HBsAg-transgenic mice with YAP inhibitor verteporfin directly suppressed the BMI1-related cell cycle. CONCLUSION: HBV-associated proliferative HCC might be related to the HBsAg-YAP-BMI1 axis and offer a potential target for the development of new therapeutic approaches.

Alcohol and its associated liver carcinogenesis.

Alcohol consumption is a major cause of cirrhosis and hepatocellular carcinoma (HCC). The prevalence of alcohol-associated hepatocellular carcinoma (aHCC) varies worldwide but is highest in Eastern Europe. Alcohol is the second fastest-growing cause of age-standardized liver cancer mortality with tumors more often diagnosed outside surveillance protocols and at a more advanced stage. Risk factors for aHCC include greater amounts of alcohol consumption, sex, and certain genetic polymorphisms. Smoking, concomitant liver disease, obesity, and diabetes act synergistically in increasing the risk of HCC in alcohol-associated liver disease. Alcohol-related hepatocarcinogenesis results from the complex interactions of several mechanistic pathways. Although not completely understood, underlying mechanisms include acetaldehyde-related hepatotoxicity, oxidative stress, activation of the innate immune system, and alterations of the host microbiome.

Oncogenic Wnt3a is a promising sensitive biomarker for monitoring hepatocarcinogenesis.

BACKGROUND: The effective treatment for hepatocellular carcinoma (HCC) depends on early diagnosis. Previously, the abnormal expression of Wnt3a as the key signaling molecule in the Wnt/ß-catenin pathway was found in HCC cells and could be released into the circulation. In this study, we used rat model of hepatocarcinogenesis to dynamically investigate the alteration of oncogenic Wnt3a and to explore its early monitor value for HCC. METHODS: Sprague-Dawley rats (SD) were fed with diet 2-fluorenylacetamide (2-FAA, 0.05%) for inducing hepatocarcinogenesis, and grouped based on liver morphological alteration by Hematoxylin & Eosin (H&E) staining; rats fed with normal chow were used as normal control (NC). Total RNA and protein were purified from rat livers. Differently expressed genes (DEGs) or Wnt3a mRNA, cellular distribution, and Wnt3a protein levels were analyzed by whole genome microarray with signal logarithm ratio (SLR log2cy5/cy3), immunohistochemistry, and enzyme-linked immunosorbent assay, respectively. RESULTS: Models of rat hepatocarcinogenesis were successfully established based on liver histopathological H&E staining. Rats were divided into the cell degeneration (rDeg), precancerosis (rPre-C) and HCC (rHCC) groups. Total numbers of the up- and down-regulated DEGs with SLR ≥ 8 were 55 and 48 in the rDeg group, 268 and 57 in the rPre-C group, and 312 and 201 in the rHCC group, respectively. Significantly altered genes were involved in cell proliferation, signal transduction, tumor metastasis, and apoptosis. Compared with the NC group, Wnt3a mRNA was increased by 4.6 folds (P < 0.001) in the rDeg group, 7.4 folds (P < 0.001) in the rPre-C group, and 10.4 folds (P < 0.001) in the rHCC group; the positive rates of liver Wnt3a were 66.7% (P = 0.001) in the rDeg group, 100% (P < 0.001) in the rPre-C group, and 100% (P < 0.001) in the rHCC group, respectively. Also, there were significant differences of liver Wnt3a (P < 0.001) or serum Wnt3a (P < 0.001) among different groups. CONCLUSIONS: Overexpression of Wnt3a was associated with rat hepatocarcinogenesis and it should be expected to be a promising monitoring biomarker for HCC occurrence at early stage.

[Role of hepatitis B virus e protein and core protein in hepatocarcinogenesis]. / Rôle des protéines HBe et HBc du virus de l'hépatite B dans l'hépatocarcinogenèse.

Chronic hepatitis B virus (HBV) infection is one of the most common factors associated with hepatocellular carcinoma (HCC). However, the pathogenesis of HBV-mediated hepatocarcinogenesis is not clearly defined. Persistence of HBV infection is associated with HCC pathogenesis, and various HBV proteins appear to be involved in promoting this persistence. Currently available data suggest that the core protein, a structural component of the viral nucleocapsid, and the HBe protein, a non-structural HBV protein that can act as both a tolerogen and an immunogen, play a potential role in the development of HCC. Research shows that both proteins are capable of disrupting various pathways involved in liver carcinogenesis, including the sustenance of proliferative signaling, resistance to cell death, tumor-promoting inflammation and avoid immune destruction. This review summarizes the various signaling pathways by which HBc and HBe proteins (and their precursors) can promote hepatocarcinogenesis.

Combined hepatocellular-cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL-6 trans-signaling.

BACKGROUND & AIMS: Primary liver cancers include hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (CCA) and combined HCC-CCA tumors (cHCC-CCA). It has been suggested, but not unequivocally proven, that hepatic progenitor cells (HPCs) can contribute to hepatocarcinogenesis. We aimed to determine whether HPCs contribute to HCC, cHCC-CCA or both types of tumors. METHODS: To trace progenitor cells during hepatocarcinogenesis, we generated Mdr2-KO mice that harbor a yellow fluorescent protein (YFP) reporter gene driven by the Foxl1 promoter which is expressed specifically in progenitor cells. These mice (Mdr2-KOFoxl1-CRE;RosaYFP) develop chronic inflammation and HCCs by the age of 14-16 months, followed by cHCC-CCA tumors at the age of 18 months. RESULTS: In this Mdr2-KOFoxl1-CRE;RosaYFP mouse model, liver progenitor cells are the source of cHCC-CCA tumors, but not the source of HCC. Ablating the progenitors, caused reduction of cHCC-CCA tumors but did not affect HCCs. RNA-sequencing revealed enrichment of the IL-6 signaling pathway in cHCC-CCA tumors compared to HCC tumors. Single-cell RNA-sequencing (scRNA-seq) analysis revealed that IL-6 is expressed by immune and parenchymal cells during senescence, and that IL-6 is part of the senescence-associated secretory phenotype. Administration of an anti-IL-6 antibody to Mdr2-KOFoxl1-CRE;RosaYFP mice inhibited the development of cHCC-CCA tumors. Blocking IL-6 trans-signaling led to a decrease in the number and size of cHCC-CCA tumors, indicating their dependence on this pathway. Furthermore, the administration of a senolytic agent inhibited IL-6 and the development of cHCC-CCA tumors. CONCLUSION: Our results demonstrate that cHCC-CCA, but not HCC tumors, originate from HPCs, and that IL-6, which derives in part from cells in senescence, plays an important role in this process via IL-6 trans-signaling. These findings could be applied to develop new therapeutic approaches for cHCC-CCA tumors. LAY SUMMARY: Combined hepatocellular carcinoma-cholangiocarcinoma is the third most prevalent type of primary liver cancer (i.e. a cancer that originates in the liver). Herein, we show that this type of cancer originates in stem cells in the liver and that it depends on inflammatory signaling. Specifically, we identify a cytokine called IL-6 that appears to be important in the development of these tumors. Our results could be used for the development of novel treatments for these aggressive tumors.

Biochemical analysis of the initial carcinogenic changes that induce preneoplastic and neoplastic cell populations during chemical hepatocarcinogenesis in rats.

To analyze the initial carcinogenic changes that induce preneoplastic and neoplastic cell populations in the rat liver, a short-term in vivo promotion assay method was developed. Preneoplastic foci and nodules were quantitated with glutathione S-transferase P-form (GST-P) and γ-glutamyl transpeptidase. Among the four agents tested, benzyl isothiocyanate (BITC) demonstrated the strongest promotor activity, producing very large nodules composed of 218 to 220 cells in the rat liver. In addition, a choline/methionine-deficient (CMD) diet, which strongly inhibits protein synthesis, exhibited lower but distinct promotive activity, giving rise to large nodules composed of 211 to 213 cells. Based on the collected stereologic and biochemical data as well as the results of DNA microarray analysis, preneoplastic foci and nodules were strongly indicated to grow without cell division. The absence of cell division indicates the absence of mutations in the genetic mechanism, and vice versa; thus, preneoplastic cell induction can be considered nongenetic. Furthermore, the nodules were markedly more susceptible to promoter agents than hepatocytes as to die of necrosis. Based on these experimental findings, neoplastic cell induction was logically deduced to be nongenetic. The present analysis may help improve the knowledge of the "unknowable mechanism of cancer initiation" of rat chemical hepatocarcinogenesis.

Changes in therapeutic options for hepatocellular carcinoma in Asia.

The incidence rate of hepatocellular carcinoma (HCC) is expected to increase, with most cases occurring in Asia. In some parts of Asia, the occurrence of HCC developing from metabolic-related liver disease has markedly increased in recent years, whereas the occurrence of HCC developing from viral-hepatitis-related liver disease has decreased. Advancements in the treatment of HCC over the past few decades has been remarkable, with most treatment strategies to remove or control liver tumours (hepatic resection, local ablation, radiation therapy, transarterial chemoembolisation, hepatic arterial infusion chemotherapy) primarily developing in Asia. In addition, recent progress in systemic therapies has prolonged the prognosis of advanced HCC. Nowadays, six regimens of systemic therapies have become available in most countries, according to phase III trials (atezolizumab plus bevacizumab, sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab). In a global randomised phase III trial (IMbrave 150 trial), the most effective of the latest drug designs was newly emerged combination immunotherapy (atezolizumab plus bevacizumab), which has shown significantly prolonged overall survival compared with sorafenib, which was the first-line systemic therapy for more than a decade. Now, the treatment dynamics for HCC are undergoing a major transition as a result of two important changes: the replacement of viral-related HCC by metabolic-related HCC and the emergence of combination immune therapy.

Plant-based foods and hepatocellular carcinoma: A review on mechanistic understanding.

Regardless of etiology, hepatocarcinogenesis is frequently preceded by a distinctive sequence of chronic necroinflammation, compensatory hepatic regeneration, development of hepatic fibrosis, and ultimately cirrhosis. The liver being central immunomodulators, closely maintains immunotolerance. Any dysregulation in this management of immunotolerance is a hallmark of chronic hepatic disease and hepatocellular carcinoma (HCC). Apart from other malignancies, hepatocellular carcinoma accounts for 90% of liver cancers. Several emerging evidences have recognized diet as lifestyle associated risk factor in HCC development. However, natural compounds have the potential to fight hepatoma aggressiveness via inhibition of cellular proliferation and modulation of oncogenic pathways. This review aimed to identify the several plant-based foods for their protective role in HCC prevention by understating the molecular mechanisms involved in inhibition of progression and proliferation of cancer. Information from relevant publications in which several plant-based foods demonstrated protective potential against HCC has been integrated as well as evaluated. For data integration, Science direct, Google scholar, and Scopus websites were used. Nutrition-based approaches in the deterrence of several cancers offer a substantial benefit to currently used medical therapies and should be implemented more often as an adjunct to first-line medical therapy. Furthermore, the inclusion of these plant-based foods (vegetables, fruits, herbs, and spices) may improve general health and decline cancer incidence.

Long-term persistence of hepatocarcinogenic potential of a non-hypervascular hypointense nodule on EOB-MRI after the eradication of hepatitis C virus.

Non-hypervascular hypointense nodules (NHHNs) on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) have a high likelihood of hypervascularization progressing to typical hypervascular hepatocellular carcinoma (HCC). NHHNs that were present before the start of anti-hepatitis C virus (HCV) therapy is a risk marker for HCC development after achieving sustained virologic response (SVR). In this report, we show a patient without a previous history of HCC in whom HCC developed by hypervascularization of NHHN after SVR. This patient achieved SVR more than 8 years before NHHN developed into HCC, and during this time NHHN had been present but had remained unchanged in size and imaging features as shown by repeated EOB-MRI. Hepatocarcinogenic potential of NHHNs persist for a long time after SVR, despite the eradication of HCV.

Extracellular microparticles derived from hepatic progenitor cells deliver a death signal to hepatoma-initiating cells.

The malignant transformation of normal resident hepatic stem/progenitor cells has a critical role in hepatocarcinogenesis and the recurrence of hepatocellular carcinoma (HCC). We defined such hepatic progenitor cells as hepatoma-initiating cells. An efficient strategy is required to target and kill the hepatoma-initiating cells. We isolated extracellular microparticles (MPs) derived from apoptotic hepatic progenitor cells (HPCs) and tested their ability to inhibit hepatocarcinogenesis. Extracellular MPs were isolated from HPCs, hepatocytes and liver tumor cells. Their effects on tumor growth were investigated in rat primary HCC models, in which hepatocarcinogenesis is induced by diethylnitrosamine (DEN). The extracellular MPs derived from apoptotic HPCs, apoptotic hepatocytes and apoptotic liver tumor cells were similar in morphology, diameter and zeta potential. However, they had different antitumor effects. In DEN-exposed rats, only the MPs derived from apoptotic HPCs effectively inhibit hepatocarcinogenesis. In vitro and in vivo analyses confirmed that HPCs preferentially take up MPs derived from apoptotic HPCs compared to MPs from other liver cell types. Proteomic analysis of MPs from apoptotic HPCs showed enrichment of proteins involved in cell death pathways. Thus, HPC-derived MPs contain a death signal to induce the killing of hepatoma-initiating cells. Our findings provide evidence that a death signal encapsulated in HPC-derived extracellular microparticles can efficiently clear hepatoma-initiating cells and prevent hepatocarcinogenesis.

Quercetin and naringenin abate diethylnitrosamine/acetylaminofluorene-induced hepatocarcinogenesis in Wistar rats: the roles of oxidative stress, inflammation and cell apoptosis.

This study was designed to assess the preventive effects and to suggest the probable mechanisms of action of quercetin and naringein in diethylnitrosamine (DEN)/2-acetylaminofluorene (2AAF)-induced hepatocarcinogenesis in Wistar male rats. The chemical-induction of hepatocarcinogenesis was performed by injection of DEN intraperitoneally at 150 mg/kg body weight (b.w.) twice/week for two weeks, followed by oral administration of 2AAF at 20 mg/kg body weight (b.w.) 4 times/week for 3 weeks. The DEN/2AAF-administered rats were co-treated with quercetin and naringenin at dose level of 10 mg/kg b. w. by oral gavage for 20 weeks. The treatment of DEN/2AAF-administered rats with quercetin and naringenin significantly prevented the elevations in serum levels of liver function indicators (ALT, AST, ALP, γ-GT, total bilirubin and albumin) and liver tumor biomarkers including AFP, CEA and CA19.9. The cancerous histological lesions and inflammatory cells infiltration in liver of DEN/2AAF-administered rats were remarkably suppressed by treatments with quercetin and naringenin. The hepatic oxidative stress markers including NO level and lipid peroxidation significantly decreased while the SOD, GPx and CAT activities and GSH content significantly increased in DEN/2AAF-administered rats treated with quercetin and naringenin when compared to DEN/2AFF-administered control rats. Furthermore, the lowered mRNA expression of liver IL-4, P53 and Bcl-2 in of DEN/2AAF-administered rats were significantly counteracted by treatment with quercetin and naringenin. Taken together, our results demonstrate that quercetin and naringenin may abate hepatocarcinogenesis via enhancement of anti-inflammatory, anti-oxidant and apoptotic actions.

Targeted Therapies for Hepatocellular Carcinoma Treatment: A New Era Ahead-A Systematic Review.

Hepatocellular carcinoma (HCC) remains one of the most common malignancies and the third cause of cancer-related death worldwide, with surgery being the best prognostic tool. Among the well-known causative factors of HCC are chronic liver virus infections, chronic virus hepatitis B (HBV) and chronic hepatitis virus C (HCV), aflatoxins, tobacco consumption, and non-alcoholic liver disease (NAFLD). There is a need for the development of efficient molecular markers and alternative therapeutic targets of great significance. In this review, we describe the general characteristics of HCC and present a variety of targeted therapies that resulted in progress in HCC therapy.

Hepatitis B Virus-Associated Hepatocellular Carcinoma and Chronic Stress.

The Hepatitis B virus is one of the most significant hepatocarcinogens globally. The carcinogenic mechanisms of this virus are complex, and may include interactions with the host's immune system. Certain factors, such as stress on the body, can also potentiate these mechanisms. Stress, although adaptive in an acute form, is deleterious to health when chronic and can both suppress and activate the host's defense system. In hepatocellular carcinoma, this can lead to tumor initiation and progression. Those that are more prone to stress, or exposed to situations that incite stress, may be at higher risk of developing cancer. Racial disparities, for example, are a source of chronic psychosocial stress in America and predispose minorities to poorer outcomes. As it remains perplexing why some individuals with chronic hepatitis B develop feared complications while others do not, it is important to recognize as many risk factors as possible, including those often overlooked such as chronic stress.

Pituitary Tumor-Transforming Gene 1/Delta like Non-Canonical Notch Ligand 1 Signaling in Chronic Liver Diseases.

The management of chronic liver diseases (CLDs) remains a challenge, and identifying effective treatments is a major unmet medical need. In the current review we focus on the pituitary tumor transforming gene (PTTG1)/delta like non-canonical notch ligand 1 (DLK1) axis as a potential therapeutic target to attenuate the progression of these pathological conditions. PTTG1 is a proto-oncogene involved in proliferation and metabolism. PTTG1 expression has been related to inflammation, angiogenesis, and fibrogenesis in cancer and experimental fibrosis. On the other hand, DLK1 has been identified as one of the most abundantly expressed PTTG1 targets in adipose tissue and has shown to contribute to hepatic fibrosis by promoting the activation of hepatic stellate cells. Here, we extensively analyze the increasing amount of information pointing to the PTTG1/DLK1 signaling pathway as an important player in the regulation of these disturbances. These data prompted us to hypothesize that activation of the PTTG1/DLK1 axis is a key factor upregulating the tissue remodeling mechanisms characteristic of CLDs. Therefore, disruption of this signaling pathway could be useful in the therapeutic management of CLDs.

[Pathology of hepatocellular carcinoma]. / Pathologie des Hepatozellulären Karzinoms.

Hepatocellular carcinoma (HCC) represents the third leading cause of cancer-related mortality worldwide and has a well-defined etiology. It develops in a stepwise process with morphologically defined precursor lesions. Typing of highly differentiated hepatocellular tumors is supported by immunohistological marker panel and the so-called matrix diagnosis. The recent World Health Organization (WHO) classification defined morpho-molecular HCC subtypes showing typical clinical and prognostic characteristics. If HCC subtyping is considered in future clinical studies of advanced HCC, this could help to introduce personalized HCC therapy. Currently, precision oncology is not available for HCC.