The Experts below are selected from a list of 249 Experts worldwide ranked by ideXlab platform
Pierre Bedossa - One of the best experts on this subject based on the ideXlab platform.
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anti angiogenic effect of metformin in human Liver Carcinogenesis related to metabolic syndrome
Gut, 2015Co-Authors: Miguel Albuquerque, Mouniya Mebarki, Pierre Bedossa, Francois Cauchy, Samira Laouirem, Pierreemmanuel Rautou, Olivier Soubrane, Eric RaymondAbstract:Dear Editor, We read with interest the work by Chen et al 1 who reported the decreased risk for developing hepatocellular carcinoma (HCC) in patients treated with metformin in a dose-dependent and time-dependent manner. Indeed, the metabolic syndrome (MS) is becoming one of the leading risk factors for Liver Carcinogenesis, mainly through the presence of diabetes.2 ,3 In addition to clinical data confirming previous studies,4 Chen et al 1 were the first to highlight experimental antitumoral effects of metformin both on hepatoma cell lines and on murine models through cell-cycle arrest via AMPK activation. However, whether these results are transposable in a clinical setting of HCC occurring in the specific context of MS has to date remained uncertain. To address this issue, we analysed a series of eight surgically resected HCC samples obtained from diabetic patients with MS preoperatively receiving (n=4) or not metformin (n=4) for antidiabetic purpose. Their clinicopathological characteristics …
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cullin7 a new gene involved in Liver Carcinogenesis related to metabolic syndrome
Gut, 2013Co-Authors: Valerie Paradis, Miguel Albuquerque, Mouniya Mebarki, Lucie Hernandez, Stephane Zalinski, Samuel Quentin, Jacques Belghiti, Jean Soulier, Pierre BedossaAbstract:Background Metabolic syndrome (MS) is an emerging risk factor in hepatocellular carcinoma (HCC). HCC related to MS may occur either in advanced fibrosis or before the development of cirrhosis, suggesting involvement of different molecular pathways according to the features of background Liver. Objective To investigate genomic aberrations in HCC related to MS in order to identify new target genes involved in Liver Carcinogenesis. Methods Chromosomal aberrations of HCC obtained from 20 patients with MS (HCC/MS) were studied by comparative genomic hybridisation and compared with HCC related to hepatitis C virus (HCV) infection (HCC/HCV, n=10) and, within the group of HCC with MS, according to the condition of the background Liver (presence or absence of significant fibrosis). Results Among the most frequent chromosomal alterations observed in HCC, 6p21.1 amplification had a higher incidence in HCC/MS than in HCC/HCV (60% vs 20%, p CUL7 downregulation using siRNA transfection in hepatoma cell lines induced significant cyclin D1 expression (by promoting its degradation), decreased cell proliferation and increased apoptosis. Conclusions This study demonstrates specific genomic alterations in HCC/MS and points to CUL7 as a novel gene potentially involved in Liver Carcinogenesis associated with MS, the amplification of which might influence cell proliferation.
Hisataka Moriwaki - One of the best experts on this subject based on the ideXlab platform.
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Sodium alginate prevents progression of non-alcoholic steatohepatitis and Liver Carcinogenesis in obese and diabetic mice
Oncotarget, 2016Co-Authors: Tsuneyuki Miyazaki, Yohei Shirakami, Masaya Kubota, Takayasu Ideta, Takahiro Kochi, Hiroyasu Sakai, Takuji Tanaka, Hisataka Moriwaki, Masahito ShimizuAbstract:// Tsuneyuki Miyazaki 1 , Yohei Shirakami 1, 2 , Masaya Kubota 1 , Takayasu Ideta 1 , Takahiro Kochi 1 , Hiroyasu Sakai 1 , Takuji Tanaka 3 , Hisataka Moriwaki 1 , Masahito Shimizu 1 1 Department of Gastroenterology/Medicine, Gifu University Graduate School of Medicine, Gifu, Japan 2 Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Japan 3 Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan Correspondence to: Yohei Shirakami, e-mail: ys2443@gifu-u.ac.jp Keywords: obesity, non-alcoholic steatohepatitis, Liver Carcinogenesis, sodium alginate, diabetes mellitus Received: November 24, 2015 Accepted: January 25, 2016 Published: February 08, 2016 ABSTRACT Obesity and related metabolic abnormalities play a key role in Liver Carcinogenesis. Non-alcoholic steatohepatitis (NASH), which is often complicated with obesity and diabetes mellitus, is associated with the development of hepatocellular carcinoma (HCC). Sodium alginate (SA), which is extracted from brown seaweeds, is marketed as a weight loss supplement because of its high viscosity and gelling properties. In the present study, we examined the effects of SA on the progression of NASH and related Liver Carcinogenesis in monosodium glutamate (MSG)-treated mice, which show obesity, diabetes mellitus, and NASH-like histopathological changes. Male MSG-mice were intraperitoneally injected with diethylnitrosamine at 2 weeks of age, and, thereafter, they received a basal diet containing high- or low-molecular-weight SA throughout the experiment (16 weeks). At sacrifice, control MSG-treated mice fed the basal-diet showed significant obesity, hyperinsulinemia, steatosis and hepatic tumor development. SA administration suppressed body weight gain; improved insulin sensitivity, hyperinsulinemia, and hyperleptinemia; attenuated inflammation in the Liver and white adipose tissue; and inhibited hepatic lipogenesis and progression of NASH. SA also reduced oxidative stress and increased anti-oxidant enzyme levels in the Liver. Development of hepatic tumors, including Liver cell adenoma and HCC, and hepatic pre-neoplastic lesions was significantly inhibited by SA supplementation. In conclusion, oral SA supplementation improves Liver steatosis, insulin resistance, chronic inflammation, and oxidative stress, preventing the development of Liver tumorigenesis in obese and diabetic mice. SA may have ability to suppress steatosis-related Liver Carcinogenesis in obese and diabetic subjects.
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Acyclic retinoid in chemoprevention of hepatocellular carcinoma: Targeting phosphorylated retinoid X receptor-α for prevention of Liver Carcinogenesis
Journal of Carcinogenesis, 2012Co-Authors: Masahito Shimizu, Yohei Shirakami, Kenji Imai, Koji Takai, Hisataka MoriwakiAbstract:One of the key features of hepatocellular carcinoma (HCC) is the high rate of intrahepatic recurrence that correlates with poor prognosis. Therefore, in order to improve the clinical outcome for patients with HCC, development of a chemopreventive agent that can decrease or delay the incidence of recurrence is a critical issue for urgent investigation. Acyclic retinoid (ACR), a synthetic retinoid, successfully improves HCC patient survival by preventing recurrence and the formation of secondary tumors. A malfunction of the retinoid X receptor-α (RXRα) due to phosphorylation by the Ras-MAPK signaling pathway plays a critical role in Liver Carcinogenesis, and ACR exerts chemopreventive effects on HCC development by inhibiting RXRα phosphorylation. Here, we review the relationship between retinoid signaling abnormalities and Liver disease, the mechanisms of how RXRα phosphorylation contributes to Liver Carcinogenesis, and the detailed effects of ACR on preventing HCC development, especially based on the results of our basic and clinical research. We also outline the concept of clonal deletion and inhibition therapy, which is defined as the removal and inhibition of latent malignant clones from the Liver before they expand into clinically detectable HCC, because ACR prevents the development of HCC by implementing this concept. Looking toward the future, we discuss combination chemoprevention using ACR as a key drug since it can generate a synergistic effect, and may thus be an effective new strategy for the prevention of HCC.
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nutraceutical approach for preventing obesity related colorectal and Liver Carcinogenesis
International Journal of Molecular Sciences, 2012Co-Authors: Masahito Shimizu, Masaya Kubota, Takuji Tanaka, Hisataka MoriwakiAbstract:Obesity and its related metabolic abnormalities, including insulin resistance, alterations in the insulin-like growth factor-1 (IGF-1)/IGF-1 receptor (IGF-1R) axis, and the state of chronic inflammation, increase the risk of colorectal cancer (CRC) and hepatocellular carcinoma (HCC). However, these findings also indicate that the metabolic disorders caused by obesity might be effective targets to prevent the development of CRC and HCC in obese individuals. Green tea catechins (GTCs) possess anticancer and chemopreventive properties against cancer in various organs, including the colorectum and Liver. GTCs have also been known to exert anti-obesity, antidiabetic, and anti-inflammatory effects, indicating that GTCs might be useful for the prevention of obesity-associated colorectal and Liver Carcinogenesis. Further, branched-chain amino acids (BCAA), which improve protein malnutrition and prevent progressive hepatic failure in patients with chronic Liver diseases, might be also effective for the suppression of obesity-related Carcinogenesis because oral supplementation with BCAA reduces the risk of HCC in obese cirrhotic patients. BCAA shows these beneficial effects because they can improve insulin resistance. Here, we review the detailed relationship between metabolic abnormalities and the development of CRC and HCC. We also review evidence, especially that based on our basic and clinical research using GTCs and BCAA, which indicates that targeting metabolic abnormalities by either pharmaceutical or nutritional intervention may be an effective strategy to prevent the development of CRC and HCC in obese individuals.
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Chemoprevention of Liver Carcinogenesis with retinoids: Basic and clinical aspects.
Hepatology Research, 2007Co-Authors: Hisataka Moriwaki, Masahito Shimizu, Masataka Okuno, Rie Nishiwaki-matsushimaAbstract:The strategy to prevent Liver Carcinogenesis consists of: (i) antiviral modalities such as vaccination, lamivudin, and interferon; (ii) anti-inflammatory modality; and (iii) chemoprevention using such compounds as retinoid analog and vitamin K. Cancer chemoprevention is defined as an approach where natural or synthetic chemical compound works to arrest or reverse premalignant cells by using physiological pathways. As a consequence, such a clone of premalignant cells is eradicated (clonal deletion) by differentiation induction or apoptosis, and thus the process toward the development of clinically detectable cancer is disrupted. A particularly effective candidate target of chemoprevention in Liver diseases is an advanced stage of chronic hepatitis, that is supposed to contain transformed hepatocyte clone(s); that is, primary prevention from Liver cirrhosis and prevention of recurrent and second primary hepatocellular carcinoma following the treatment of the initial cancer. Retinoid is a collective term of vitamin A analog that binds to nuclear retinoid receptors;retinoic acid receptors (RAR) and retinoid X receptors (RXR). After ligand coupling, these receptors form homo- or heterodimers, bind to the response element (RARE or RXRE) upstream of the target gene, and regulate the gene expression as a transcriptional factor. Biological phenotypes of such transcriptional regulation by retinoid include cellular differentiation, tissue morphogenesis, and programmed cell death (apoptosis). Due to these functions, retinoid analogs are clinically tried to prevent/treat carcinoma in a wide variety of organs including head and neck cancer, uterine cervical cancer, certain leukemia and Liver cancer. In this article, clinical trials of retinoid analog to inhibit second primary hepatoma, supposed molecular mechanism of the action of the compound, and aberrant metabolism of RXR and its role in Liver Carcinogenesis are briefly reviewed.
Masahito Shimizu - One of the best experts on this subject based on the ideXlab platform.
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Sodium alginate prevents progression of non-alcoholic steatohepatitis and Liver Carcinogenesis in obese and diabetic mice
Oncotarget, 2016Co-Authors: Tsuneyuki Miyazaki, Yohei Shirakami, Masaya Kubota, Takayasu Ideta, Takahiro Kochi, Hiroyasu Sakai, Takuji Tanaka, Hisataka Moriwaki, Masahito ShimizuAbstract:// Tsuneyuki Miyazaki 1 , Yohei Shirakami 1, 2 , Masaya Kubota 1 , Takayasu Ideta 1 , Takahiro Kochi 1 , Hiroyasu Sakai 1 , Takuji Tanaka 3 , Hisataka Moriwaki 1 , Masahito Shimizu 1 1 Department of Gastroenterology/Medicine, Gifu University Graduate School of Medicine, Gifu, Japan 2 Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Japan 3 Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan Correspondence to: Yohei Shirakami, e-mail: ys2443@gifu-u.ac.jp Keywords: obesity, non-alcoholic steatohepatitis, Liver Carcinogenesis, sodium alginate, diabetes mellitus Received: November 24, 2015 Accepted: January 25, 2016 Published: February 08, 2016 ABSTRACT Obesity and related metabolic abnormalities play a key role in Liver Carcinogenesis. Non-alcoholic steatohepatitis (NASH), which is often complicated with obesity and diabetes mellitus, is associated with the development of hepatocellular carcinoma (HCC). Sodium alginate (SA), which is extracted from brown seaweeds, is marketed as a weight loss supplement because of its high viscosity and gelling properties. In the present study, we examined the effects of SA on the progression of NASH and related Liver Carcinogenesis in monosodium glutamate (MSG)-treated mice, which show obesity, diabetes mellitus, and NASH-like histopathological changes. Male MSG-mice were intraperitoneally injected with diethylnitrosamine at 2 weeks of age, and, thereafter, they received a basal diet containing high- or low-molecular-weight SA throughout the experiment (16 weeks). At sacrifice, control MSG-treated mice fed the basal-diet showed significant obesity, hyperinsulinemia, steatosis and hepatic tumor development. SA administration suppressed body weight gain; improved insulin sensitivity, hyperinsulinemia, and hyperleptinemia; attenuated inflammation in the Liver and white adipose tissue; and inhibited hepatic lipogenesis and progression of NASH. SA also reduced oxidative stress and increased anti-oxidant enzyme levels in the Liver. Development of hepatic tumors, including Liver cell adenoma and HCC, and hepatic pre-neoplastic lesions was significantly inhibited by SA supplementation. In conclusion, oral SA supplementation improves Liver steatosis, insulin resistance, chronic inflammation, and oxidative stress, preventing the development of Liver tumorigenesis in obese and diabetic mice. SA may have ability to suppress steatosis-related Liver Carcinogenesis in obese and diabetic subjects.
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Acyclic retinoid in chemoprevention of hepatocellular carcinoma: Targeting phosphorylated retinoid X receptor-α for prevention of Liver Carcinogenesis
Journal of Carcinogenesis, 2012Co-Authors: Masahito Shimizu, Yohei Shirakami, Kenji Imai, Koji Takai, Hisataka MoriwakiAbstract:One of the key features of hepatocellular carcinoma (HCC) is the high rate of intrahepatic recurrence that correlates with poor prognosis. Therefore, in order to improve the clinical outcome for patients with HCC, development of a chemopreventive agent that can decrease or delay the incidence of recurrence is a critical issue for urgent investigation. Acyclic retinoid (ACR), a synthetic retinoid, successfully improves HCC patient survival by preventing recurrence and the formation of secondary tumors. A malfunction of the retinoid X receptor-α (RXRα) due to phosphorylation by the Ras-MAPK signaling pathway plays a critical role in Liver Carcinogenesis, and ACR exerts chemopreventive effects on HCC development by inhibiting RXRα phosphorylation. Here, we review the relationship between retinoid signaling abnormalities and Liver disease, the mechanisms of how RXRα phosphorylation contributes to Liver Carcinogenesis, and the detailed effects of ACR on preventing HCC development, especially based on the results of our basic and clinical research. We also outline the concept of clonal deletion and inhibition therapy, which is defined as the removal and inhibition of latent malignant clones from the Liver before they expand into clinically detectable HCC, because ACR prevents the development of HCC by implementing this concept. Looking toward the future, we discuss combination chemoprevention using ACR as a key drug since it can generate a synergistic effect, and may thus be an effective new strategy for the prevention of HCC.
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nutraceutical approach for preventing obesity related colorectal and Liver Carcinogenesis
International Journal of Molecular Sciences, 2012Co-Authors: Masahito Shimizu, Masaya Kubota, Takuji Tanaka, Hisataka MoriwakiAbstract:Obesity and its related metabolic abnormalities, including insulin resistance, alterations in the insulin-like growth factor-1 (IGF-1)/IGF-1 receptor (IGF-1R) axis, and the state of chronic inflammation, increase the risk of colorectal cancer (CRC) and hepatocellular carcinoma (HCC). However, these findings also indicate that the metabolic disorders caused by obesity might be effective targets to prevent the development of CRC and HCC in obese individuals. Green tea catechins (GTCs) possess anticancer and chemopreventive properties against cancer in various organs, including the colorectum and Liver. GTCs have also been known to exert anti-obesity, antidiabetic, and anti-inflammatory effects, indicating that GTCs might be useful for the prevention of obesity-associated colorectal and Liver Carcinogenesis. Further, branched-chain amino acids (BCAA), which improve protein malnutrition and prevent progressive hepatic failure in patients with chronic Liver diseases, might be also effective for the suppression of obesity-related Carcinogenesis because oral supplementation with BCAA reduces the risk of HCC in obese cirrhotic patients. BCAA shows these beneficial effects because they can improve insulin resistance. Here, we review the detailed relationship between metabolic abnormalities and the development of CRC and HCC. We also review evidence, especially that based on our basic and clinical research using GTCs and BCAA, which indicates that targeting metabolic abnormalities by either pharmaceutical or nutritional intervention may be an effective strategy to prevent the development of CRC and HCC in obese individuals.
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Chemoprevention of Liver Carcinogenesis with retinoids: Basic and clinical aspects.
Hepatology Research, 2007Co-Authors: Hisataka Moriwaki, Masahito Shimizu, Masataka Okuno, Rie Nishiwaki-matsushimaAbstract:The strategy to prevent Liver Carcinogenesis consists of: (i) antiviral modalities such as vaccination, lamivudin, and interferon; (ii) anti-inflammatory modality; and (iii) chemoprevention using such compounds as retinoid analog and vitamin K. Cancer chemoprevention is defined as an approach where natural or synthetic chemical compound works to arrest or reverse premalignant cells by using physiological pathways. As a consequence, such a clone of premalignant cells is eradicated (clonal deletion) by differentiation induction or apoptosis, and thus the process toward the development of clinically detectable cancer is disrupted. A particularly effective candidate target of chemoprevention in Liver diseases is an advanced stage of chronic hepatitis, that is supposed to contain transformed hepatocyte clone(s); that is, primary prevention from Liver cirrhosis and prevention of recurrent and second primary hepatocellular carcinoma following the treatment of the initial cancer. Retinoid is a collective term of vitamin A analog that binds to nuclear retinoid receptors;retinoic acid receptors (RAR) and retinoid X receptors (RXR). After ligand coupling, these receptors form homo- or heterodimers, bind to the response element (RARE or RXRE) upstream of the target gene, and regulate the gene expression as a transcriptional factor. Biological phenotypes of such transcriptional regulation by retinoid include cellular differentiation, tissue morphogenesis, and programmed cell death (apoptosis). Due to these functions, retinoid analogs are clinically tried to prevent/treat carcinoma in a wide variety of organs including head and neck cancer, uterine cervical cancer, certain leukemia and Liver cancer. In this article, clinical trials of retinoid analog to inhibit second primary hepatoma, supposed molecular mechanism of the action of the compound, and aberrant metabolism of RXR and its role in Liver Carcinogenesis are briefly reviewed.
Igor P. Pogribny - One of the best experts on this subject based on the ideXlab platform.
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microrna deregulation in nonalcoholic steatohepatitis associated Liver Carcinogenesis
Oncotarget, 2017Co-Authors: Aline De Conti, Volodymyr Tryndyak, Frederick A. Beland, Ivan Rusyn, Juliana Festa Ortega, Kostiantyn Dreval, Fernando Salvador Moreno, Igor P. PogribnyAbstract:// Aline de Conti 1, * , Juliana Festa Ortega 1, 2, * , Volodymyr Tryndyak 1 , Kostiantyn Dreval 1 , Fernando Salvador Moreno 2 , Ivan Rusyn 3 , Frederick A. Beland 1 and Igor P. Pogribny 1 1 Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas, USA 2 Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil 3 Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA * These authors have contributed equally to this work Correspondence to: Igor P. Pogribny, email: igor.pogribny@fda.hhs.gov Keywords: hepatoCarcinogenesis, non-alcoholic steatohepatitis, epigenetics, microRNAs, miR-93-5p Received: June 20, 2017 Accepted: July 06, 2017 Published: August 01, 2017 ABSTRACT Hepatocellular carcinoma (HCC) is the fastest-rising cause of cancer-related death in the United States. Recent epidemiological studies have identified nonalcoholic steatohepatitis (NASH), a progressive form of nonalcoholic fatty Liver disease (NAFLD), as a major risk factor for HCC. Elucidating the underlying mechanisms associated with the development of NASH-derived HCC is critical for identifying early biomarkers for the progression of the disease and for treatment and prevention. In the present study, using Liver samples from C57BL/6J mice submitted to the Stelic Animal Model (STAM) of NASH-associated Liver Carcinogenesis, we investigated the role of microRNA (miRNA) alterations in the pathogenesis of NASH-derived HCC. We found substantial alterations in the expression of miRNAs, with the greatest number occurring in full-fledged HCC. Mechanistically, altered miRNA expression was associated with activation of major hepatoCarcinogenesis-related pathways, including the TGF-β, Wnt/β-catenin, ERK1/2, mTOR, and EGF signaling. In addition, the over-expression of the miR-221-3p and miR-222-3p and oncogenic miR-106b~25 cluster was accompanied by the reduced protein levels of their targets, including E2F transcription factor 1 (E2F1), phosphatase and tensin homolog (PTEN), and cyclin-dependent kinase inhibitor 1 (CDKN1A). Importantly, miR-93-5p, miR-221-3p, and miR-222-3p were also significantly over-expressed in human HCC. These findings suggest that aberrant expression of miRNAs may have mechanistic significance in NASH-associated Liver Carcinogenesis and may serve as an indicator for the development of NASH-derived HCC.
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Differentially expressed MicroRNAs provide mechanistic insight into fibrosis-associated Liver Carcinogenesis in mice.
Molecular Carcinogenesis, 2015Co-Authors: April K. Marrone, Svitlana Shpyleva, Grace A. Chappell, Volodymyr Tryndyak, Takeki Uehara, Masato Tsuchiya, Frederick A. Beland, Ivan Rusyn, Igor P. PogribnyAbstract:Hepatocellular carcinoma (HCC) is one of the most prevalent human cancers, with a rising incidence worldwide. The molecular mechanisms associated with the development of HCC are complex and include multiple interconnected molecular alterations with mounting evidence indicating an important role of microRNAs (miRNAs) in the pathogenesis of HCC. In humans, the development of HCC is commonly associated with Liver cirrhosis. To study fibrosis-associated Liver Carcinogenesis, we used a mouse model designed to emulate the development of HCC in cirrhotic Liver. Specifically, we were interested in evaluating the role of miRNAs in the molecular pathogenesis of Liver Carcinogenesis in male B6C3F1/J mice treated with N-nitrosodiethylamine (DEN) or carbon tetrachloride (CCl4) alone or a combination of DEN and CCl4 and characterized by a differential tumor incidence that increased in the following order: DEN
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molecular mechanisms of fibrosis associated promotion of Liver Carcinogenesis
Toxicological Sciences, 2013Co-Authors: Takeki Uehara, Igor P. Pogribny, Levan Muskhelishvili, Garrett R Ainslie, Kristi Kutanzi, Takeshi Izawa, Jyoji Yamate, Oksana Kosyk, Svitlana Shymonyak, Blair U BradfordAbstract:The incidence of Liver cancer, including hepatocellular carcinoma (HCC), continues to increase worldwide, most prominently in the developed countries in North America, Europe, and Oceania (Center and Jemal, 2011). Major etiological factors contributing to HCC are well established and include viral infections, excessive ethanol consumption, environmental carcinogens, and hemochromatosis (El-Serag and Rudolph, 2007; Farazi and DePinho, 2006). More recently, metabolic diseases related to insulin resistance collectively identified as nonalcoholic steatohepatitis have been recognized to be causally related to HCC as well (Della Corte and Colombo, 2012). Still, the understanding of HCC pathogenesis and the mechanisms of tumor development is incomplete (Fausto and Campbell, 2010; Vucur et al., 2010). Animal models, most often rat or mouse, are commonly used to understand the molecular pathogenesis of HCC (Heindryckx et al., 2009), as well as to test for the cancer hazard potential of chemicals and drugs (Wells and Williams, 2009). Liver is the most common tissue for tumor development in experimental rodent studies of chronic exposure to xenobiotics (Hoenerhoff et al., 2011; Huff et al., 1991). However, the overwhelming majority of the positive (i.e., significant increases in the incidence of Liver adenomas and carcinomas) chronic rodent cancer studies fail to produce Liver fibrosis or cirrhosis. In cases when cirrhotic changes are observed in rodent Liver in association with development of hepatocellular neoplasms (e.g., thioacetamide and N-nitrosomorpholine), high necrogenic doses were applied (Becker, 1983; Oh et al., 2002). Lack of fibrosis and cirrhosis in most positive 2-year cancer bioassays in rodents is in stark contrast to human HCC where Liver cirrhosis is both the most common histopathological feature observed in subjects with HCC and an important mechanism of hepatoCarcinogenesis (Farazi and DePinho, 2006). In fact, the incidence of HCC in noncirrhotic human Livers is estimated at only 15–20% of all cases, and in the Livers that are devoid of any signs of chronic disease, the incidence is even lower at about 10% (Alkofer et al., 2011). Thus, among many limitations, chronic rodent cancer bioassays do not address this key feature of human HCC. Although mechanistic studies of chemical Carcinogenesis in the Liver have been largely replaced in the past decade by the genetically modified mouse models (Lee et al., 2004), testing of chemicals for cancer hazard continues to be conducted in B6C3F1 mouse hybrid strain, rather than in genetically altered mouse models (Bucher, 1998). Given the importance of Liver cirrhosis in the development of human HCC, integrative studies that evaluate the mechanisms of fibrogenesis, and how they relate to hepatocyte transformation and modulation of oncogenic signaling, are most relevant to better understanding of the pathogenesis of human disease. These goals can be best achieved by animal models that, as much as possible, mimic molecular pathogenesis of Liver disease leading to HCC development in humans, where a combination of etiological factors such as genotoxic injury and advanced fibrosis is likely to be in play (Fausto and Campbell, 2010). Accordingly, this study used a well-known model of Liver Carcinogenesis induced by a single injection of a low-dose genotoxic agent diethylnitrosamine (DEN) into 14-day-old male mice (Druckrey et al., 1964; Vesselinovitch and Mihailovich, 1983). Then, repeat dosing of the profibrogenic agent carbon tetrachloride (CCl4) was performed, starting at 8 weeks of age for up to 14 consecutive weeks. We observed that in mice initiated with DEN, chronic Liver fibrosis led to dramatic potentiation of the Liver tumor incidence where 100% of the animals had developed Liver tumors at 5 months of age. In addition, we show that in DEN-treated animals, this promotional effect on Liver Carcinogenesis was associated with the induction of cancer stem cells in noncancerous Liver tissue, rather than an effect on Liver inflammation, fibrogenesis, oxidative stress, proliferation, or apoptosis.
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Abstract 5556: Role of the aberrant intracellular iron metabolism in rat Liver Carcinogenesis
Cancer Research, 2011Co-Authors: Svitlana Shpyleva, Volodymyr Tryndyak, Frederick A. Beland, Levan Muskhelishvili, Igor P. PogribnyAbstract:Intracellular iron homeostasis in normal cells is tightly regulated by the coordination of several proteins that are responsible for the uptake, intracellular storage, and removal of iron from cells. Cancer cells, including Liver cancer cells, are characterized by profound abberations in intracellular iron metabolism. Dysregulated iron homeostasis has been found not only in rodent and human hepatocellular carcinomas, but also in several preneoplastic pathological states associated with Liver cancer development; however, the precise mechanistic role of iron metabolic disturbances in the initiation and early progression of Liver Carcinogenesis has remained unexplored. In the present study, using an in vivo model of rat hepatoCarcinogenesis induced by 2-acetylaminofluorene, we found extensive alterations in cellular iron metabolism at preneoplastic stages of Liver Carcinogenesis characterized by a substantial decrease in the levels of cytoplasmic non-heme iron in initiated hepatocytes and altered expression of the major genes responsible for the proper maintenance of accurate intracellular homeostasis. Specifically, analysis of the gene expression patterns revealed prominent up-regulation of the ferroportin (Fpn) gene and down-regulation of the hepcidin (Hamp) gene in the preneoplastic Livers. This indicates that the decreased intracellular levels of non-heme iron in preneoplastic foci may be attributed to increased iron export from the cells driven by the loss of an inhibitory effect of hepcidin on Fpn. This suggestion is supported by a substantial up-regulation of Fpn (3-fold) compared to transferrin receptor (Tfrc) gene, (1.6 fold), the latter of which is responsible for the iron intake into cell. These data indicate that in preneoplastic Livers there is a disruption in the balance of regulatory networks controlling cellular iron uptake and export. Interestingly, we detected similar gene expression changes in initiated preneoplastic Liver cells that were transformed by culturing of non-tumorigenic TRL-1215 rat Liver cells in the presence of iron. In conclusion, our results demonstrate the significance of altered intracellular iron metabolism in the progression of Liver Carcinogenesis and suggest that correction of these alterations may affect Liver cancer development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5556. doi:10.1158/1538-7445.AM2011-5556
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Role of DNA damage and alterations in cytosine DNA methylation in rat Liver Carcinogenesis induced by a methyl-deficient diet.
Mutation research, 2009Co-Authors: Igor P. Pogribny, Svitlana I Shpyleva, Levan Muskhelishvili, Tetyana V Bagnyukova, S Jill James, Frederick A. BelandAbstract:Currently, cancer is recognized as a disease provoked by both genetic and epigenetic events. However, the significance of early genetic and epigenetic alterations with respect to carcinogenic process in general and to Liver Carcinogenesis in particular remains unexplored. A lack of knowledge regarding how specific alterations during early preneoplasia may be mechanistically related to tumor formation creates a major gap in understanding the role of these genetic and epigenetic abnormalities in Carcinogenesis. In the present study we investigated the contribution of DNA damage and epigenetic alterations to Liver Carcinogenesis induced by a methyl-deficient diet. Feeding Fisher 344 rats a methyl-deficient diet for 9 weeks resulted in DNA damage and aberrant DNA methylation. This was evidenced by an early up-regulation of the base excision DNA repair genes, accumulation of 8-oxodeoxyguanosine and 3'OH-end strand breaks in DNA, pronounced global loss of DNA methylation, and hypermethylation of CpG islands in the Livers of methyl-deficient rats. These abnormalities were completely restored in the Livers of rats exposed to methyl-deficiency for 9 weeks after removal of the methyl-deficient diet and re-feeding a methyl-sufficient diet. However, when rats were fed a methyl-deficient diet for 18 week and then given a methyl-sufficient diet, only DNA lesions were repaired. The methyl-sufficient diet failed to restore completely the altered DNA methylation status and prevent the progression of Liver Carcinogenesis. These results suggest that stable alterations in DNA methylation are a factor that promotes the progression of Liver Carcinogenesis. Additionally, the results indicate that epigenetic changes may be more reliable markers than DNA lesions of the carcinogenic process and carcinogen exposure.
Peter Schirmacher - One of the best experts on this subject based on the ideXlab platform.
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obesity promotes Liver Carcinogenesis via mcl 1 stabilization independent of il 6rα signaling
Cell Reports, 2013Co-Authors: Sabine Gruber, Beate K Straub, Justus P Ackermann, Claudia M Wunderlich, Jan Mauer, Jens M Seeger, Hildegard Buning, Lukas Heukamp, Hamid Kashkar, Peter SchirmacherAbstract:Summary Obesity increases the incidence of hepatocellular carcinoma (HCC) development in part through the activation of obesity-associated proinflammatory signaling. Here, we show that in lean mice, abrogation of IL-6Rα signaling protects against diethylnitrosamine (DEN)-induced HCC development. HCC protection occurs via Mcl-1 destabilization, thus promoting hepatocyte apoptosis. IL-6 regulates Mcl-1 stability via the inhibition of PP-1α expression, promoting GSK-3β inactivation. In addition, IL-6 suppresses expression of the Mcl-1 E3 ligase (Mule). Consequently, IL-6Rα deficiency activates PP-1α and Mule expression, resulting in increased Mcl-1 turnover and protection against HCC development. In contrast, in obesity, inhibition of PP-1α and Mule expression, leading to Mcl-1 stabilization, occurs independently of IL-6 signaling. Collectively, this study provides evidence that obesity inhibits hepatocyte apoptosis through Mcl-1 stabilization independent of IL-6 signaling, thus promoting Liver Carcinogenesis.
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s100a8 and s100a9 are novel nuclear factor kappa b target genes during malignant progression of murine and human Liver Carcinogenesis
Hepatology, 2009Co-Authors: Julia Nemeth, Ilan Stein, Daniel Haag, Astrid Riehl, Thomas Longerich, Elad Horwitz, Kai Breuhahn, Christoffer Gebhardt, Peter SchirmacherAbstract:The nuclear factor-kappaB (NF-κB) signaling pathway has been recently shown to participate in inflammation-induced cancer progression. Here, we describe a detailed analysis of the NF-κB–dependent gene regulatory network in the well-established Mdr2 knockout mouse model of inflammation-associated Liver Carcinogenesis. Expression profiling of NF-κB–deficient and NF-κB–proficient hepatocellular carcinoma (HCC) revealed a comprehensive list of known and novel putative NF-κB target genes, including S100a8 and S100a9. We detected increased co-expression of S100A8 and S100A9 proteins in mouse HCC cells, in human HCC tissue, and in the HCC cell line Hep3B on ectopic RelA expression. Finally, we found a synergistic function for S100A8 and S100A9 in Hep3B cells resulting in a significant induction of reactive oxygen species (ROS), accompanied by enhanced cell survival. Conclusion: We identified S100A8 and S100A9 as novel NF-κB target genes in HCC cells during inflammation-associated Liver Carcinogenesis and provide experimental evidence that increased co-expression of both proteins supports malignant progression by activation of ROS-dependent signaling pathways and protection from cell death. (HEPATOLOGY 2009.)