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Journal of Hepatocellular Carcinoma 2022Hepatocellular carcinoma (HCC) is the most common type of primary liver cancers. It is an aggressive neoplasm with dismal outcome because most of the patients present...
INTRODUCTION
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancers. It is an aggressive neoplasm with dismal outcome because most of the patients present with an advanced-stage disease, which precludes curative surgical options. Therefore, these patients require systemic therapies that typically induce small improvements in overall survival. Hence, it is crucial to identify new and promising therapeutic targets for HCC to improve the current outcome. The liver is a key organ in the signaling cascade triggered by the growth hormone receptor (GHR). Previous studies have shown that GHR signaling stimulates the proliferation and regeneration of liver cells and tissues; however, a definitive role of GHR signaling in HCC pathogenesis has not been identified.
METHODS
In this study, we used a direct and specific approach to analyze the role of GHR in HCC development. This approach encompasses mice with global ( ) or liver-specific ( ) disruption of GHR expression, and the injection of diethylnitrosamine (DEN) to develop HCC in these mice.
RESULTS
Our data show that DEN induced HCC in a substantial majority of the (93.5%) and (87.1%) mice but not in the (5.6%) mice (P < 0.0001). Although 57.7% of mice developed HCC after injection of DEN, these mice had significantly fewer tumors than (P < 0.001), which implies that the expression of GHR in the liver cells might increase tumor burden. Notably, the pathologic, histologic, and biochemical characteristics of DEN-induced HCC in mice resembled to a great extent human HCC, despite the fact that etiologically this model does not mimic this cancer in humans. Our data also show that the effects of DEN on mice livers were primarily related to its carcinogenic effects and ability to induce HCC, with minimal effects related to toxic effects.
CONCLUSION
Collectively, our data support an important role of GHR in HCC development, and suggest that exploiting GHR signaling may represent a promising approach to treat HCC.
PubMed: 35996397
DOI: 10.2147/JHC.S368208 -
Hepatology Communications Nov 2022Phospholipase C gamma 1 (PLCγ1) plays an oncogenic role in several cancers, alongside its usual physiological roles. Despite studies aimed at identifying the effect of...
Phospholipase C gamma 1 (PLCγ1) plays an oncogenic role in several cancers, alongside its usual physiological roles. Despite studies aimed at identifying the effect of PLCγ1 on tumors, the pathogenic role of PLCγ1 in the tumorigenesis and development of hepatocellular carcinoma (HCC) remains unknown. To investigate the function of PLCγ1 in HCC, we generated hepatocyte-specific PLCγ1 conditional knockout (PLCγ1 ; Alb-Cre) mice and induced HCC with diethylnitrosamine (DEN). Here, we identified that hepatocyte-specific PLCγ1 deletion effectively prevented DEN-induced HCC in mice. PLCγ1 ; Alb-Cre mice showed reduced tumor burden and tumor progression, as well as a decreased incidence of HCC and less marked proliferative and inflammatory responses. We also showed that oncogenic phenotypes such as repressed apoptosis, and promoted proliferation, cell cycle progression and migration, were induced by PLCγ1. In terms of molecular mechanism, PLCγ1 regulated the activation of signal transducer and activator of transcription 3 (STAT3) signaling. Moreover, PLCγ1 expression is elevated in human HCC and correlates with a poor prognosis in patients with HCC. Our results suggest that PLCγ1 promotes the pathogenic progression of HCC, and PLCγ1/STAT3 axis was identified as a potential therapeutic target pathway for HCC.
Topics: Humans; Mice; Animals; STAT3 Transcription Factor; Carcinoma, Hepatocellular; Diethylnitrosamine; Liver Neoplasms; Phospholipase C gamma; Cell Proliferation; Carcinogenesis
PubMed: 36153805
DOI: 10.1002/hep4.2077 -
Journal of Caffeine and Adenosine... Mar 2019Adenosine kinase (ADK) is a key regulator of hepatic metabolism. Its deficiency in the liver causes hepatic steatosis and methylation defects. In this study, we...
Adenosine kinase (ADK) is a key regulator of hepatic metabolism. Its deficiency in the liver causes hepatic steatosis and methylation defects. In this study, we investigated whether reduced ADK expression affects the susceptibility of the liver to a carcinogen. We investigated ADK expression in samples from 11 liver cancer patients. We used transgenic Adk-tg mice with reduced hepatic ADK to study their susceptibility to a carcinogen. We exposed 45 Adk-tg and 21 wild-type (WT) mice to the carcinogen diethylnitrosamine (DEN) and the tumor promoter phenobarbital (PB) and examined the survival and body weight. Seven of 11 patients with liver cancer had reduced ADK expression. A Kaplan-Meier survival curve showed a significantly increased mortality rate of DEN/PB-exposed Adk-tg mice compared with WT mice. Reduced hepatic ADK increases the susceptibility to the acute toxic effects of a carcinogen. Low hepatic ADK might be a risk factor and biomarker for cancer development.
PubMed: 30944910
DOI: 10.1089/caff.2018.0019 -
Archives of Medical Science : AMS 2021Curcumin therapeutic applications are constrained by its prominent metabolic instability as well as inadequate absorption and bioavailability. The current study was...
INTRODUCTION
Curcumin therapeutic applications are constrained by its prominent metabolic instability as well as inadequate absorption and bioavailability. The current study was designed to enhance the curcumin bioavailability by exploiting nanoparticles.
MATERIAL AND METHODS
Eleven groups of mice were divided into: normal and nanoparticle control groups, a hepatocellular carcinoma (HCC) group induced by diethylnitrosamine (DEN), 2 groups treated with DEN plus a high dose/low dose of free curcumin, 2 groups treated with a high dose/low dose of free curcumin, 2 groups treated with DEN plus a high dose/low dose of nanoparticulate curcumin, and 2 groups treated with a high dose/low dose of nanoparticulate curcumin.
RESULTS
DEN administration significantly increased liver enzymes, vascular endothelial growth factor, tumor necrosis factor-α, α-fetoprotein, malondialdehyde, and nucelar factor-κB. Also, it decreased serum albumin and tissue antioxidant activities and caused severe histological changes in hepatic tissue. Oral treatment of DEN-injected mice with either a high dose of free curcumin or the tested doses of nanoparticulate curcumin resulted in a significant improvement of all the tested parameters.
CONCLUSIONS
Although the two tested doses of nanoparticulate curcumin were much lower than free curcumin, both doses were effective in preventing HCC development while the low dose of free curcumin was hardly effective. Hence, we conclude that nanoparticles enhance the bioavailability of curcumin.
PubMed: 33488874
DOI: 10.5114/aoms.2020.93739 -
The Journal of Experimental Medicine May 2017Human hepatocellular carcinomas (HCCs), which arise on a background of chronic liver damage and inflammation, express c-Fos, a component of the AP-1 transcription...
Human hepatocellular carcinomas (HCCs), which arise on a background of chronic liver damage and inflammation, express c-Fos, a component of the AP-1 transcription factor. Using mouse models, we show that hepatocyte-specific deletion of c-Fos protects against diethylnitrosamine (DEN)-induced HCCs, whereas liver-specific c-Fos expression leads to reversible premalignant hepatocyte transformation and enhanced DEN-carcinogenesis. c-Fos-expressing livers display necrotic foci, immune cell infiltration, and altered hepatocyte morphology. Furthermore, increased proliferation, dedifferentiation, activation of the DNA damage response, and gene signatures of aggressive HCCs are observed. Mechanistically, c-Fos decreases expression and activity of the nuclear receptor LXRα, leading to increased hepatic cholesterol and accumulation of toxic oxysterols and bile acids. The phenotypic consequences of c-Fos expression are partially ameliorated by the anti-inflammatory drug sulindac and largely prevented by statin treatment. An inverse correlation between c-FOS and the LXRα pathway was also observed in human HCC cell lines and datasets. These findings provide a novel link between chronic inflammation and metabolic pathways important in liver cancer.
Topics: Animals; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Cholesterol; Diethylnitrosamine; Disease Models, Animal; Drosophila Proteins; Liver; Liver Neoplasms; Mice; Proto-Oncogene Proteins c-fos; Repressor Proteins
PubMed: 28356389
DOI: 10.1084/jem.20160935 -
Iranian Journal of Basic Medical... Jan 2020Resveratrol (RSV) is a naturally occurring plant polyphenol with cardioprotective, neuroprotective, immunoregulatory, and anticancer properties and is biologically...
OBJECTIVES
Resveratrol (RSV) is a naturally occurring plant polyphenol with cardioprotective, neuroprotective, immunoregulatory, and anticancer properties and is biologically effective against various diseases. This study aimed to investigate the chemopreventive effect of different doses of RSV against hepatocellular carcinoma (HCC) induced by diethylnitrosamine (DEN) in rats.
MATERIALS AND METHODS
The rats were randomly divided into six groups of seven rats each (n=42). The control group (group 1) was injected with saline, group 2 with dimethyl sulfoxide (DMSO), group 3 with DEN, group 4 with DEN and 50 mg/kg of RSV (DEN+RSV 50), group 5 with DEN and 75 mg/kg of RSV (DEN+RSV 75), and group 6 with DEN and 100 mg/kg of RSV (DEN+RSV 100). Pro-apoptotic Bax/anti-apoptotic Bcl-2 and tumor suppressor p53 markers were analyzed by immunostaining.
RESULTS
Superoxide dismutase, glutathione, and malondialdehyde concentrations were not statistically significant in DEN+RSV 100 group but were closest to the concentrations in control group. Liver function tests showed that enzyme activity (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and γ-glutamyl transferase) increased in DEN+RSV 50 and DEN+RSV 100 groups compared with control group but decreased in DEN+RSV 50 and DEN+RSV 100 groups compared with DEN group. Bax/Bcl-2 and p53 analysis showed a statistically significant increase in apoptotic cells in DEN+RSV 100 group.
CONCLUSION
A 100 mg/kg dose of RSV may be a promising treatment for HCC.
PubMed: 32405350
DOI: 10.22038/IJBMS.2019.36821.8774 -
Integrative Cancer Therapies Nov 2015Hepatocellular carcinoma (HCC) is one of the common cancers and lethal diseases worldwide. Both oxidative stress and chronic inflammation contribute to the pathogenesis...
Hepatocellular carcinoma (HCC) is one of the common cancers and lethal diseases worldwide. Both oxidative stress and chronic inflammation contribute to the pathogenesis of HCC. Because of limited treatment options and a grave prognosis of HCC, preventive management has been emphasized. The marine macroalgae Ulva lactuca (Ulvaceae) is consumed by humans and livestock because of its nutritional value. Recent studies showed that various extracts of U. lactuca possess antiviral, antiplasmodial, antinephrotoxic, antioxidant, and anti-inflammatory properties. However, very limited information is available on anticancer potential of U. lactuca with no reports on liver cancer chemopreventive efficacy of this marine algae. Accordingly, the present study was initiated to evaluate the possible antihepatocarcinogenic effects and antioxidant mechanisms of action of various U. lactuca extracts against a clinically relevant rodent model of HCC. Initiation of hepatocarcinogenesis was performed in Sprague-Dawley rats by a single injection of dietary carcinogen diethylnitrosamine (DENA, 200 mg/kg, intraperitoneally), followed by promotion with phenobarbital (0.05%) in drinking water. The rats were fed with daily oral dose (50 mg/kg) of polysaccharide sulfate or aqueous extract of U. lactuca for 2, 12, and 24 weeks. At these timepoints, blood samples were taken to measure hepatic injury markers, including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transferase, and bilirubin. The liver tissue was harvested for measurement of hepatic oxidative indices, including lipid peroxidation, reduced glutathione, nitric oxide, catalase, superoxide dismutase, glutathione reductase, and glutathione S-transferase. Hepatic histopathology, immunohistochemical analysis of cell proliferation and apoptosis by DNA fragmentation assay were performed. Our results clearly indicate that sulfated polysaccharides of U. lactuca exert a marked chemoprevention of DENA-initiated hepatocarcinogenesis through inhibition of abnormal cell proliferation and induction of apoptosis. A modest inhibition rat liver carcinogenesis was observed with the aqueous extract. The sulfated polysaccharides altered serum parameters of hepatic damage and modulated various components of the hepatic enzymatic and nonenzymatic antioxidant defense systems. The sulfated polysaccharides from U. lactuca may have unique properties of providing protection against DENA-induced oxidative stress which could contribute to chemoprevention of experimental hepatocarcinogenesis. U. lactuca sulfated polysaccharides could be developed as chemopreventive and therapeutic drug against human HCC.
Topics: Animals; Anticarcinogenic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Proliferation; Diethylnitrosamine; Liver Neoplasms, Experimental; Male; Oxidative Stress; Phenobarbital; Plant Extracts; Polysaccharides; Rats; Rats, Sprague-Dawley; Time Factors; Ulva
PubMed: 26130745
DOI: 10.1177/1534735415590157 -
Cell Death & Disease Feb 2018G-protein-coupled receptor (GPCR)-related proteins are dysregulated and the GPCR CC-chemokine receptor 10 (CCR10) is significantly upregulated in inflammation-driven...
G-protein-coupled receptor (GPCR)-related proteins are dysregulated and the GPCR CC-chemokine receptor 10 (CCR10) is significantly upregulated in inflammation-driven HCC. However, CCR10's role in inflammation-driven hepatocarcinogenesis remains unknown. The aim of this study was to evaluate the role of CCR10 in inflammation-driven hepatocarcinogenesis. Via a targeted gene expression microarray screening alterations in GPCR family gene expression, we found CCR10 to be significantly upregulated in hepatocytes isolated from inflammation-driven human HCC tumors and matching paracancerous tissues. Tetrachloromethane (CCl4)-induced and diethylnitrosamine (DEN)-induced murine models of inflammatory hepatocarcinogenesis displayed significant hepatocellular TNF and CCR10 upregulation. Exogenous TNF applied to HepG2 and LO2 cell lines as well as wild-type (WT) mice significantly upregulated hepatocellular CCR10 expression, Akt phosphorylation, PCNA expression, and hepatocellular proliferation. Additionally, exogenous TNF significantly upregulated secretion of the natural CCR10 ligand-agonist CCL28 from both cell lines. Transgenic CCR10-knockout (CCR10 KO) in DEN-treated mice significantly increased hepatocellular apoptosis levels and significantly lowered compensatory hepatocellular proliferation but did not affect upstream TNF expression. In addition, DEN-treated CCR10 KO mice showed a significantly lower liver weight/body weight ratio, significantly lower liver tumor incidence, and significantly smaller tumors. Moreover, exogenous CCR10 expression significantly raised xenograft tumor growth in Balb/c nude mice. In vitro, CCR10 transfection or CCL28 treatment in HepG2 and LO2 cell lines significantly increased Akt phosphorylation, PCNA expression, and cell proliferation, while CCR10 silencing or Akt inhibition produced the opposite effects. In vivo, hepatocytes isolated from HCC tumor tissue and matching paracancerous tissue in DEN-treated CCR10 KO mice showed significantly lower Akt phosphorylation and PCNA expression relative to WT hepatocytes. In conclusion, inflammation-induced TNF promotes hepatocellular CCR10 expression and downstream PI3K/Akt-mediated hepatocarcinogenesis. CCR10 appears to function as a linkage between TNF stimulation and downstream PI3K/Akt pathway activation and shows promise as a potential therapeutic target for inflammation-driven HCC.
Topics: Adolescent; Adult; Aged; Animals; Apoptosis; Carbon Tetrachloride; Carcinogenesis; Carcinoma, Hepatocellular; Cell Line, Tumor; Chemokines, CC; Diethylnitrosamine; Female; Gene Expression Regulation, Neoplastic; Hemangioma; Humans; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Mice; Mice, Nude; Middle Aged; Phosphatidylinositol 3-Kinases; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins c-akt; Receptors, CCR10; Signal Transduction; Tumor Necrosis Factor-alpha
PubMed: 29445190
DOI: 10.1038/s41419-018-0267-9 -
Biochemical Pharmacology Apr 2024The worst-case scenario related to alcoholic liver disease (ALD) arises after a long period of exposure to the harmful effect of alcohol consumption along with other...
The worst-case scenario related to alcoholic liver disease (ALD) arises after a long period of exposure to the harmful effect of alcohol consumption along with other hepatotoxics. ALD encompasses a broad spectrum of liver-associated disorders, such as steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Based on the chronic administration of different hepatotoxics, including ethanol, sucrose, lipopolysaccharide, and low doses of diethylnitrosamine over a short period, here we aimed to develop a multiple hepatotoxic (MHT)-ALD model in the mouse that recapitulates the human ALD-associated disorders. We demonstrated that the MHT-ALD model induces ADH1A and NXN, an ethanol metabolizer and a redox-sensor enzyme, respectively; promotes steatosis associated with the induction of the lipid droplet forming FSP27, inflammation identified by the infiltration of hepatic neutrophils-positive to LY-6G marker, and the increase of MYD88 level, a protein involved in inflammatory response; and stimulates the early appearance of cellular senescence identified by the senescence markers SA-β-gal activity and p-H2A.X. It also induces fibrosis associated with increased desmin, a marker of hepatic stellate cells whose activation leads to the deposition of collagen fibers, accompanied by cell death and compensatory proliferation revealed by increased CASP3-mediated apoptosis, and KI67- and PCNA-proliferation markers, respectively. It also induces histopathological traits of malignancy and the level of the HCC marker, GSTP1. In conclusion, we provide a useful model for exploring the chronological ALD-associated alterations and stages, and addressing therapeutic approaches.
PubMed: 38621424
DOI: 10.1016/j.bcp.2024.116209 -
Cancer Prevention Research... Jun 2020Hepatocellular carcinoma (HCC) is a highly morbid condition with lack of effective treatment options. HCC arises from chronically inflamed and damaged liver tissue;...
Hepatocellular carcinoma (HCC) is a highly morbid condition with lack of effective treatment options. HCC arises from chronically inflamed and damaged liver tissue; therefore, chemoprevention may be a useful strategy to reduce HCC incidence. Several reports suggest that epigallocatechin gallate (EGCG), extracted from green tea, can suppress liver inflammation and fibrosis in animal models, but its role in HCC chemoprevention is not well established. In this study, male Wistar rats were injected with diethylnitrosamine at 50 mg/kg for 18 weeks to induce cirrhosis and HCC, and EGCG was given in drinking water at a concentration of 0.02%. Clinically achievable dosing of EGCG was well-tolerated in diethylnitrosamine-injured rats and was associated with improved serum liver markers including alanine transaminase, aspartate transaminase, and total bilirubin, and reduced HCC tumor formation. Transcriptomic analysis of diethylnitrosamine-injured hepatic tissue was notable for increased expression of genes associated with the Hoshida high risk HCC gene signature, which was prevented with EGCG treatment. EGCG treatment also inhibited fibrosis progression, which was associated with inactivation of hepatic stellate cells and induction of the senescence-associated secretory phenotype. In conclusion, EGCG administered at clinically safe doses exhibited both chemopreventive and antifibrotic effects in a rat diethylnitrosamine liver injury model.
Topics: Animals; Anticarcinogenic Agents; Biomarkers; Carcinoma, Hepatocellular; Catechin; Cellular Senescence; Diethylnitrosamine; Hepatic Stellate Cells; Liver Cirrhosis; Liver Neoplasms, Experimental; Male; Phenotype; Precancerous Conditions; Rats; Tea; Transcriptome
PubMed: 32253266
DOI: 10.1158/1940-6207.CAPR-19-0383