Insight into the impact of diabetes mellitus on the increased risk of hepatocellular carcinoma: mini-review
© Ali Kamkar et al.; licensee BioMed Central Ltd. 2014
Received: 30 October 2013
Accepted: 2 May 2014
Published: 22 May 2014
Hepatocellular carcinoma is a multifactorial disease which is associated with a background of many causal risk factors. Diabetes mellitus however is one of the most common co-morbid illnesses found in hepatocellular carcinoma patients that are significantly associated with worsening of hepatocellular carcinoma development, patient prognosis and survival. Therefore, efforts have been focused on understanding the mechanisms underlying progression of hepatocellular carcinoma onset and development especially in diabetic patients. To our knowledge, there are no reports which address the impact of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) along with epigenetic regulations associated with increased risk of hepatocellular carcinoma confounded by diabetes mellitus. Therefore, this mini-review focuses on the possible intermediary mechanisms involved in worsening the onset and progression of hepatocellular carcinoma development confounded by diabetes mellitus. The first approach is to look at the role of inflammatory mediators (TNF-α and IL-6) in apoptosis and inflammation during hepatocarcinogenesis through monitoring levels of apoptotic regulators, B-cell lymphoma 2 protein which is encoded by BCL2 gene and apoptosis regulator BAX known as bcl-2-like protein 4 which is encoded by the BAX gene. The second approach is to focus on the possible epigenomic reprogramming that drives hepatocellular transformation since epigenetic modification of DNA is a key feature in the pathogenesis of hepatocarcinogenesis. Both approaches may suggest role of using Bcl2 and Bax as apoptotic and inflammatory markers for hepatocellular carcinoma detection as well as the importance impact of DNA methylation, hypomethylation or histone modifications as attractive candidates for early-detection biomarkers of hepatocellular carcinoma.
KeywordsApoptosis and inflammation Diabetes mellitus DNA methylation or histone modifications Epigenomic reprogramming Hepatocarcinogenesis Hepatocellular carcinoma
The association between diabetes mellitus and the risk of hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is the fifth most common malignancy in the world with high morbidity and mortality but its pathogenesis remains unclear . Because primary liver cancer is a growing concern showing poor prognosis due to its rapid infiltrating power and complicating liver cirrhosis; more attention were given to address the causal risk factors that could be preventable and/or treatable . Several risk factors have been identified that contribute to the international burden of HCC such as chronic infection with hepatitis B virus (HBV) and hepatitis C virus (HCV), alcoholic liver disease, non-alcoholic steatohepatitis (NASH), diabetes mellitus (DM), obesity, intake of aflatoxins-contaminated food, tobacco smoking, excessive alcohol drinking and genetically inherited disorders (hemochromatosis, α-1 anti-trypsin deficiency, porphyrias); . HCC is phenotypically and genetically heterogeneous tumor, reflecting in part the heterogeneity of etiologic factors involved in (i) the onset of HCC development that is also influenced by age, gender and ethnic differences, (ii) the complexity of hepatocyte functions and epigenome leading to neoplastic transformation and (iii) the late stage of HCC development .
Because the liver plays a crucial role in glucose metabolism, it is not surprising that DM is an epiphenomenon of many chronic liver diseases such as chronic hepatitis, fatty liver, liver failure and cirrhosis . DM is a metabolic disorder characterized by hyperglycemia which may predispose the liver to relative insulin resistant due to inadequate secretion or receptor insensitivity to endogenous insulin. DM is one of the leading causes of blindness and the most common cause of end-stage renal disease and cardiovascular complications in developed countries. In recent years, DM has been associated with increase risk for several malignancies including breast, colon, kidney, liver, endometrium and pancreatic cancers . In addition, DM as part of the insulin resistance syndrome, has been implicated as a risk factor for non-alcoholic fatty liver disease (NAFLD), including its most severe form non-alcoholic steatohepatitis (NASH); which has been identified as a cause of both cryptogenic cirrhosis and HCC. DM has been reported to cause a 2.5-fold greater risk of HCC, however this significant association was independent to hepatitis viral infections (HBV and/or HCV) or alcohol consumption as examined from 10 previously reported studies; those reports account for ~90% of HCC cases [1, 6]. Many case reports and case reviews of HCC in NASH have showed the association of DM and obesity on the increased risk of HCC and have implicated age and advanced fibrosis as significant risks. Insulin resistance and the resulting inflammatory cascade, which are associated with the development of NASH appears to mediate hepatocarcinogenesis in HCC .
The association between DM and HCC has been demonstrated in both case–control and cohort studies, suggesting that DM is independent risk factor for the development of HCC. These several lines of evidence includes; (i) findings that insulin resistance and DM were shown to increase the progression of liver diseases that preceded the development of HCC [6, 7]; (ii) findings showing that 2.5 fold increase in the risk of HCC was reported in patients with DM [8, 9] attributed with the prolonged DM disease duration [10–12]; (iii) findings demonstrating the synergistic interaction between DM and other HCC risk factors [11, 13, 14]; (iv) findings showed significant association of DM for the recurrence of HCC after treatment [15, 16]; (v) findings suggesting significant biological plausibility underlying the association between DM and HCC [7, 17].
Nevertheless, the exact pathophysiological mechanisms of this significant association are still unclear. In this mini-review, we aim to further analyze this relationship by evaluating the role of possible intermediary mechanisms that could be associated with the onset and progression of HCC development in the presence of DM. We will mainly focus on; (i) pro-inflammatory gene products (TNF-α and IL-6) and (ii) the epigenetic pathogenesis of DM on the development of HCC.
Possible intermediary mechanisms involved in worsening the onset and progression of hepatocellular carcinoma confounded by diabetes mellitus
TNF-α/ NF-kβ and IL-6/STAT-3 signaling pathways effect on hepatocellular carcinoma development
Malignant transformation of hepatocytes may occur through a pathway of increased liver cell turnover induced by chronic liver injury and regeneration in the context of inflammation, immune response and oxidative DNA damage . This is evidence to suggest that chronic inflammation in the individuals with diabetes mellitus type 2 (T2DM) may influence certain cancers via cytokines. Cancerous and precancerous tissue show signs of inflammation, which is caused by the infiltration of the immune cells into the tissues. The presence of inflammatory cytokines is important constituents of the local environment of tumors in certain type of cancer including HCC. These cytokines cause oncogenic changes that promote tumor development by blocking apoptosis and increasing the survival of malignant cells . Although an elevation in the circulating levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-12 (IL-12), interleukin-1-beta (IL-1β) and transforming growth factor beta (TGF-β-1) has been observed in obese and diabetic individuals [20–24]; plasma levels of interleukin-10 (IL-10) were found elevated in obese individuals thus, decreased in diabetics .
Cytokines such as IL-1β, TNF-α, IL-8 and IL-6 have been involved in chronic liver inflammation and pathogenesis of various liver diseases; among which IL-6 and TNF-α, are thought to be most important [26–28]. In this regard, TNF-α and IL-6 were found to positively correlated with the progression of HCC development in humans [29–31].
IL-6 is a pleiotropic cytokine secreted by T cells, macrophages, kupffer cells, and adipose tissue. Similarly, TNF-α is secreted by several inflammatory cell types, including monocyte/macrophages, neutrophils, T-cells, kupffer cells and adipose tissue [26, 32]. Increased circulating levels of IL-6 and TNF-α have been found in animal models and patients with liver disease including HCC . Moreover, studies have revealed that the levels of TNF-α and IL-6 are significantly increased in rats bearing hepatoma, which reflects an aggressive inflammatory response correlated with tumor induction . In obesity and DM, tremendous amount of the tumor-promoting cytokines IL-6 and TNF-α are produced, which is thought to promote HCC development [35, 31]. Moreover, DM-mediated inflammatory responses lead to the production of cytokines, which act as growth and angiogenic factors for transformed cells. DM has confounding effects on the factors of inflammation, proliferation and anti-apoptosis in HCC, which explains why HCC and DM co-occur twice as frequently as expected. Furthermore, it has been reported that diabetic patients with HCC are suffer more frequently with liver injury and tumor growth as compared to non-diabetics .
Epigenomic reprogramming that drives hepatocellular transformation
Multifactorial diseases such as DM and HCC are far more complex compared to single gene disorders; whereby multiple genes in addition to non-genetic components dictate the pathogenic manifestations of the disease. Further sophistication layer is added onto these disorders from modifications on the genetic material in cells and tissues. These are referred to as “epigenetics factors”. Epigenetic (meaning “above” genetics) inheritance is essential for the development of critical cellular processes such as gene transcription, differentiation and protection against viral genomes. Aberrant epigenetic states may predispose to genetic changes or vice versa [54–56]. Therefore, epigenetic and genetic mechanisms may work together to silence key cellular genes and destabilize the genome, leading to oncogenic transformation and observed complexity and heterogeneity in human cancers. The main epigenetic modifications that can alter gene expression and tissue-specific cellular changes  are DNA methylations, histone modifications, and non-coding RNAs (micro and long non-coding RNAs); that together impact on transcriptional regulation of wide range of genes [58, 59]. Thus, unregulated epigenetic events play key role in pathogenic mechanisms affecting the expression of many genes including tumor-suppressor genes and cancer-associated genes as has been observed in broad human cancers . Moreover, a number of studies suggested that a frequent loss of heterozygosity (LOH) in chromosome 8p in HCC cases which leads to inactivation of the Deleted in Liver Cancer 1 gene (DLC-1) may play a pivotal role in HCC development . Thus, in the late stage of HCC development; somatic mutations in several tumor suppressor genes (such as TP53, p16 and RB); oncogenes (such as c-MYC and β-catenin) and other cancer-associated genes including E-cadherin and cyclin D1 have also been observed. However, the significance and sequence of these genetic events remain to be established [61, 62].
Recent data suggest that the epigenetic pattern is age-dependent influencing key mitochondrial respiratory chain genes [63, 64]. An example is the complex 4 COX7A1 protein (which is a target of age-related DNA methylation) as evidenced from its expression reduction in muscle tissue from diabetic patients [64, 65]. In young and elderly twin studies; COX7A1 gene promoter methylation was shown to be increased in skeletal muscles of elderly compared with young twins, and that was reciprocal to expression pattern of COX7A1 gene. The transcript level of COX7A1 gene in skeletal muscle was associated with increased in vivo glucose uptake . Polymorphism can also lead to generation of DNA methylation sites (CpG dinucleotides). In addition, putative transcription factor binding site in the NDUFB6 promoter are associated with increased DNA methylation, decreased gene expression, and decreased in vivo metabolism with increasing age . The impact of aging on T2DM is also evident from data on the hepatic function of glucokinase enzyme glucose utilization, where its activity is decreased in the diabetic patients’ liver . Further evidence for epigenetic role was demonstrated in a recent study in which significant differential DNA methylation profiling was indicated when comparing pancreatic islets from type 2 diabetics with non-diabetic controls; where 276 CpG loci associated with 254 genes were uncovered. These methylation signatures were absent in peripheral blood cells of diabetic individuals, and couldn’t be experimentally induced in non-diabetic islets by exposure to high glucose, suggesting tissue-specific methylation patterns . There is also the potential role for epigenetic control microRNAs (miRNAs) on chromatin-modifying enzymes leading to effects in gene expression. Histone modifications and changes in chromatin structure can affect transcription and expression of miRNAs ; which are associated with the regulation of pathogenic pathways critical in insulin secretion, cholesterol synthesis and fat metabolism [70–72]. Increased telomeric activity and hTERT expression in HCC cases were also reported. In one study on 106 hepatic tissues with and without HCC; hTERT expression has correlated inversely with DNA methylation levels in normal tissues compared to tumor tissues in a mechanism thought to be regulated by DNA methylation and histone H3-K9 modifications .
Furthermore, genome-wide oncogenes promoter demethylation was detected during HCC progression . This demethylation was accompanied by selective regional hypermethylation in the CpG islands leading to silencing of antitumor genes like tumor suppressor genes, proliferation inhibitor genes, in addition to apoptotic and DNA repair genes [75, 76]. A proposed mechanism for HCC is suggested to occur via activating inflammatory response components’ (NF-κB and JAK/STAT) to induce epigenetic changes resulting in switching on the long-term oncogenic memory system in hepatocytes . The epigenetic switch in turn would contribute to a chronic inflammatory response during the course of altered gene expression concordant with a positive feedback loop to aggravate a chronic state of inflammation. These uncontrolled epigenetic-driven transcriptional alterations ultimately promote hepatocytes proliferative and oncogenic transformations.
Inflammatory markers (TNF-α and IL-6) can be suggested to be used as diagnostic tools for HCC along with alpha-fetoprotein (AFP) that may help to monitor the severity of hepatocellular damage and hepatic function in diabetic patients. These markers can also help to follow-up patients diagnosed with HCC prognostically. On the other hand, epigenetic alterations could be used as biomarkers of early-detection for HCC which may help in prognosticate diabetic patient outcomes or even as novel therapeutic compounds. However, large-scale prospective data is warranted before this approach can be translated into personalized medicine.
Other members who contributed in reviewing the manuscript are, Dr. Ali Tiss, Mr. Amro Shehabeldin, Dr. Mohammed Abufarha and Dr. Amal Hasan.
- Montella M, Crispo A, Giudice A: HCC, diet and metabolic factors. Hepat Mon 2011, 11: 159–162.PubMedPubMed CentralGoogle Scholar
- Sanyal AJ, Yoon SK, Lencioni R: The etiology of hepatocellular carcinoma and consequences for treatment. Oncologist 2010, 15: 14–22. 10.1634/theoncologist.2010-S4-14View ArticlePubMedGoogle Scholar
- Nordenstedt H, White DL, El-Serag HB: The changing pattern of epidemiology in hepatocellular carcinoma. Dig Liver Dis 2010, 42(Suppl 3):S206-S214.View ArticlePubMedPubMed CentralGoogle Scholar
- Baffy G: Editorial: hepatocellular carcinoma in type 2 diabetes: more than meets the eye. Am J Gastroenterol 2012, 107: 53–55. 10.1038/ajg.2011.390View ArticlePubMedGoogle Scholar
- Herman WH, Zimmet P: Type 2 diabetes: an epidemic requiring global attention and urgent action. Diabetes Care 2012, 35: 943–944. 10.2337/dc12-0298View ArticlePubMedPubMed CentralGoogle Scholar
- El-Serag HB, Hampel H, Javadi F: The association between diabetes and hepatocellular carcinoma: a systemic review of epidemiology evidence. Clin Gastroenterol Hepatol 2006, 4: 369–380. 10.1016/j.cgh.2005.12.007View ArticlePubMedGoogle Scholar
- Bell DS, Allbright E: The multifaceted associations of hepatobiliary disease and diabetes. Endocr Pract 2007, 13: 300–312. 10.4158/EP.13.3.300View ArticlePubMedGoogle Scholar
- Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serage HB: Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study. Gut 2005, 54: 533–539. 10.1136/gut.2004.052167View ArticlePubMedPubMed CentralGoogle Scholar
- Veldt BJ, Chen W, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP, Knegt RJ, Zeuzem S, Manns MP, Hansen BE, Schalm SW, Janssen HL: Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus. Hepatology 2008, 47: 1856–1862. 10.1002/hep.22251View ArticlePubMedGoogle Scholar
- Hassan MM, Curley SA, Li D, Kaseb A, Davila M, Abdalla EK, Javle M, Moghazy DM, Lozano RD, Abbruzzese JL, Vauthey JN: Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma. Cancer 2010, 116: 1938–1946. 10.1002/cncr.24982View ArticlePubMedPubMed CentralGoogle Scholar
- Yuan JM, Govindarajan S, Arakawa K, Yu MC: Synergism of alcohol, diabetes and viral hepatitis on the risk of hepatocellular carcinoma in blacks and whites in the U.S. Cancer 2004, 101: 1009–1017. 10.1002/cncr.20427View ArticlePubMedGoogle Scholar
- El-Serag HB, Tran T, Everhart JE: Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004, 126: 460–468. 10.1053/j.gastro.2003.10.065View ArticlePubMedGoogle Scholar
- Chen CL, Yang HI, Yang WS, Liu CJ, Chen PJ, You SL, Wang LY, Sun CA, Lu SN, Chen DS, Chen CJ: Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow-up study in Taiwan. Gastroenterology 2008, 135: 111–121. 10.1053/j.gastro.2008.03.073View ArticlePubMedGoogle Scholar
- Hassan MM, Hwang LY, Hatten CJ, Swaim M, Li D, Abbruzzese JL, Beasley P, Patt YZ: Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology 2002, 361: 1206–1213.View ArticleGoogle Scholar
- Komura T, Mizukoshi E, Kita Y, Sakurai M, Takata Y, Arai K, Yamashita T, Ohta T, Shimizu K, Nakamoto Y, Honda M, Takamura T, Kaneko S: Impact of diabetes on recurrence of hepatocellular carcinoma after surgical treatment in patients with viral hepatitis. Am J Gastroenterol 2007, 102: 1939–1946. 10.1111/j.1572-0241.2007.01354.xView ArticlePubMedGoogle Scholar
- Ikeda Y, Shimada M, Hasegawa H, Gion T, Kajiyama K, Shirabe K, Yanaga K, Takenaka K, Sugimachi K: Prognosis of hepatocellular carcinoma with diabetes mellitus after hepatic resection. Hepatology 1998, 27: 1567–1571. 10.1002/hep.510270615View ArticlePubMedGoogle Scholar
- Dellon ES, Shaheen NJ: Diabetes and hepatocellular carcinoma: associations, biological plausibility and clinical implications. Gastroenterology 2005, 129: 1132–1134. 10.1053/j.gastro.2005.06.079View ArticlePubMedGoogle Scholar
- El-Serag H, Rudolph K: Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007, 132: 2557–2576. 10.1053/j.gastro.2007.04.061View ArticlePubMedGoogle Scholar
- Lin WW, Karin M: A cytokine-mediated link between innate immunity, inflammation and cancer. J Clin Invest 2007, 117: 1175–1183. 10.1172/JCI31537View ArticlePubMedPubMed CentralGoogle Scholar
- Bastard JP, Jardel C, Bruckert E, Blondy P, Capeau J, Laville M, Vidal H, Hainque B: Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. J Clin Endocrinol Metab 2000, 58: 3338–3342.Google Scholar
- Thomas HE, Irawaty W, Darwiche R, Brodnicki TC, Santamaria P, Allison J, Kay TW: IL-1 receptor deficiency slows progression to diabetes in the NOD mouse. Diabetes 2004, 53: 113–121. 10.2337/diabetes.53.1.113View ArticlePubMedGoogle Scholar
- Fain JN: Release of inflammatory mediators by humuna adipose tissue is enhanced in obesity and primarily by the nonfat cells: a review. Mediators Inflamm 2010, 2010: 513948.View ArticlePubMedPubMed CentralGoogle Scholar
- Goyal R, Faizy AF, Siddiqui SS, Singhai M: Evaluation of TNF-α and IL-6 levels in obese and Non-obese diabetics: pre- and postinsulin effects. North Am J Med Sci 2012, 4: 180–184. 10.4103/1947-2714.94944View ArticleGoogle Scholar
- Pfeiffer A, Middelberg-Bisping K, Drewes C, Schatz H: Elevated plasma levels of transforming growth factor-beta 1 in NIDDM. Diabetes Care 1996, 19: 1113–1117. 10.2337/diacare.19.10.1113View ArticlePubMedGoogle Scholar
- Straczkowski M, Kowalska I, Nikolajuk A, Krukowska A, Gorska M: Plasma interleukin-10 concentration is positively related to insulin sensitivity in young healthy individuals. Diabetes Care 2005, 28: 2036–2037. 10.2337/diacare.28.8.2036View ArticlePubMedGoogle Scholar
- Montecucco F, Mach F: Does non-alcoholic fatty liver disease (NAFLD) increase cardiovascular risk? Endocr Metab Immune Disord Drug Targets 2008, 8: 301–307. 10.2174/187153008786848268View ArticlePubMedGoogle Scholar
- Lesmana CR, Hasan I, Budihusodo U, Gani RA, Krisnuhoni E, Akbar N, Lesmana LA: Diagnostic value of a group of biochemical markers of liver fibrosis in patients with non-alcoholic steatohepatitis. J Dig Dis 2009, 10: 201–206. 10.1111/j.1751-2980.2009.00386.xView ArticlePubMedGoogle Scholar
- Kishimoto T: IL-6: from its discovery to clinical applications. Int Immunol 2010, 22: 347–352. 10.1093/intimm/dxq030View ArticlePubMedGoogle Scholar
- Nakagawa H, Maeda S, Yoshida H, Tateishi R, Masuzaki R, Ohki T, Hayakawa Y, Kinoshita H, Yamakado M, Kato N, Shiina S, Omata M: Serum IL-6 levels and the risk for hepatocarcinogenesis in chronic hepatitis C patients: an analysis based on gender differences. Int J Cancer 2009, 125: 2264–2269. 10.1002/ijc.24720View ArticlePubMedGoogle Scholar
- Wong VW, Yu J, Cheng AS, Wong GL, Chan HY, Chu ES, Ng EK, Chan FK, Sung JJ, Chan HL: High serum interleukin-6 level predicts future hepatocellular carcinoma development in patients with chronic hepatitis B. Int J Cancer 2009, 124: 2766–2770. 10.1002/ijc.24281View ArticlePubMedGoogle Scholar
- Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, Österreicher CH, Takahashi H, Karin M: Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 2010, 140: 197–208. 10.1016/j.cell.2009.12.052View ArticlePubMedPubMed CentralGoogle Scholar
- Braunersreuther V, Viviani GL, Mach F, Montecucco F: Role of cytokines and chemokines in non-alcoholic fatty liver disease. World J Gastroenterol 2012, 18: 727–735. 10.3748/wjg.v18.i8.727View ArticlePubMedPubMed CentralGoogle Scholar
- Kugelmas M, Hill DB, Vivian B, Marsano L, McClain CJ: Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology 2003, 38: 413–419.View ArticlePubMedGoogle Scholar
- Abdel-Hamid NM, Nazmy MH, Abdel-Ghany MI, Nazmy WH: Cytokines as important playmakers of experimental hepatocarcinogenesis confounded by diabetes. Ann Hepatol 2012, 11: 118–127.PubMedGoogle Scholar
- Hotamisligil GS, Shargill NS, Spiegelman BM: Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993, 259: 87–91. 10.1126/science.7678183View ArticlePubMedGoogle Scholar
- Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, Karin M: Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 2007, 317: 121–124. 10.1126/science.1140485View ArticlePubMedGoogle Scholar
- Sheweita SA, Tilmisany AK: Cancer and phase II drug-metabolizing enzymes. Curr Drug Metab 2003, 4: 45–58. 10.2174/1389200033336919View ArticlePubMedGoogle Scholar
- Yu H, Pardoll D, Jove R: STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 2009, 9: 798–809. 10.1038/nrc2734View ArticlePubMedGoogle Scholar
- Hedvat M, Huszar D, Herrmann A, Gozgit JM, Schroeder A, Sheehy A, Buettner R, Proia D, Kowolik CM, Xin H, Armstrong B, Bebernitz G, Weng S, Wang L, Ye M, McEachern K, Chen H, Morosini D, Bell K, Alimzhanov M, Ioannidis S, McCoon P, Cao ZA, Yu H, Jove R, Zinda M: The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors. Cancer Cell 2009, 16: 487–497. 10.1016/j.ccr.2009.10.015View ArticlePubMedPubMed CentralGoogle Scholar
- Hong F, Kim WH, Tian Z, Jaruga B, Ishac E, Shen X, Gao B: Elevated interleukin-6 during ethanol consumption acts as a potential endogenous protective cytokine against ethanol-induced apoptosis in the liver: involvement of induction of Bcl-2 and Bcl-x (L) proteins. Oncogene 2002, 21: 32–43. 10.1038/sj.onc.1205016View ArticlePubMedGoogle Scholar
- Aggarwal BB, Kunnumakkara AB, Harikumar KB, Gupta SR, Tharakan ST, Koca C, Dey S, Sung B: Signal transducer and activator of transcription-3, inflammation, and cancer: how intimate is the relationship? Ann N Y Acad Sci 2009, 1171: 59–76. 10.1111/j.1749-6632.2009.04911.xView ArticlePubMedPubMed CentralGoogle Scholar
- Zhang X, Tachibana S, Wang H, Hisada M, Williams GM, Gao B, Sun Z: Interleukin-6 is an important mediator for mitochondrial DNA repair after alcoholic liver injury in mice. Hepatology 2010, 52: 2137–2147. 10.1002/hep.23909View ArticlePubMedPubMed CentralGoogle Scholar
- Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, Gutkovich-Pyest E, Urieli-Shoval S, Galun E, Ben-Neriah Y: NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 2004, 431: 461–466. 10.1038/nature02924View ArticlePubMedGoogle Scholar
- Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G: Inflammation and cancer: how hot is the link? Biochem Pharmacol 2006, 72: 1605–1621. 10.1016/j.bcp.2006.06.029View ArticlePubMedGoogle Scholar
- Jiang R, Xia Y, Li J, Deng L, Zhao L, Shi J, Wang X, Sun B: High expression levels of IKKalpha and IKKbeta are necessary for the malignant properties of liver cancer. Int J Cancer 2010, 126: 1263–1274.View ArticlePubMedGoogle Scholar
- Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE: Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 2005, 11: 183–190. 10.1038/nm1166View ArticlePubMedPubMed CentralGoogle Scholar
- Wullaert A, van Loo G, Heyninck K, Beyaert R: Hepatic tumor necrosis factor signaling and nuclear factor-kappaB: effects on liver homeostasis and beyond. Endocr Rev 2007, 28: 365–386. 10.1210/er.2006-0031View ArticlePubMedGoogle Scholar
- Karin M, Lin A: NF-kappaB at the crossroads of life and death. Nat Immunol 2002, 3: 221–227.View ArticlePubMedGoogle Scholar
- Szlosarek PW, Balkwill FR: Tumour necrosis factor alpha: a potential target for the therapy of solid tumours. Lancet Oncol 2003, 4: 565–573. 10.1016/S1470-2045(03)01196-3View ArticlePubMedGoogle Scholar
- Dandona P, Weinstock R, Thusu K, Abdel-Rahman E, Aljada A, Wadden T: Tumor necrosis factor-alpha in sera of obese patients: fall with weight loss. J Clin Endocrinol Metab 1998, 83: 2907–2910.PubMedGoogle Scholar
- Muto Y, Sato S, Watanabe A, Moriwaki H, Suzuki K, Kato A, Kato M, Nakamura T, Higuchi K, Nishiguchi S, Kumada H, Ohashi Y, Long-Term Survival Study (LOTUS) Group: Overweight and obesity increase the risk for liver cancer in patients with liver cirrhosis and long-term oral supplementation with branched-chain amino acid granules inhibits liver carcinogenesis in heavier patients with liver cirrhosis. Hepatol Res 2006, 35: 204–214.PubMedGoogle Scholar
- Dinh W, Füth R, Nickl W, Krahn T, Ellinghaus P, Scheffold T, Bansemir L, Bufe A, Barroso MC, Lankisch M: Elevated plasma levels of TNF-alpha and interleukin-6 in patients with diastolic dysfunction and glucose metabolism disorders. Cardiovasc Diabetol 2009, 8: 58. 10.1186/1475-2840-8-58View ArticlePubMedPubMed CentralGoogle Scholar
- He G, Yu GY, Temkin V, Ogata H, Kuntzen C, Sakurai T, Sieghart W, Peck-Radosavljevic M, Leffert HL, Karin M: Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell 2010, 17: 286–297. 10.1016/j.ccr.2009.12.048View ArticlePubMedPubMed CentralGoogle Scholar
- Baylin SB: DNA methylation and gene silencing in cancer. Nat Clin Pract Oncol 2005, 2(Suppl 1):S4-S11.View ArticlePubMedGoogle Scholar
- Herceg Z: Epigenetics and cancer: towards an evaluation of the impact of environmental and dietary factors. Mutagenesis 2007, 22: 91–103. 10.1093/mutage/gel068View ArticlePubMedGoogle Scholar
- Vaissiere T, Sawan C, Herceg Z: Epigenetic interplay between histone modifications and DNA methylation in gene silencing. Mutat Res 2008, 659: 40–48. 10.1016/j.mrrev.2008.02.004View ArticlePubMedGoogle Scholar
- Wolffe AP, Guschin D: Review: chromatin structural features and targets that regulate transcription. J Struct Biol 2000, 129: 102–122. 10.1006/jsbi.2000.4217View ArticlePubMedGoogle Scholar
- Agarwal S, Rao A: Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. Immunity 1998, 9: 765–775. 10.1016/S1074-7613(00)80642-1View ArticlePubMedGoogle Scholar
- Rao A, Avni O: Molecular aspects of T-cell differentiation. Br Med Bull 2000, 56: 969–984. 10.1258/0007142001903634View ArticlePubMedGoogle Scholar
- Pogribny IP: Epigenetic events in tumorigenesis: putting the pieces together. Exp Oncol 2010, 32: 132–136.PubMedGoogle Scholar
- Herath NI, Leggett BA, MacDonald GA: Review of genetic and epigenetic alterations in hepatocarcinogenesis. J Gastroenterol Hepatol 2006, 21: 15–21. 10.1111/j.1440-1746.2005.04043.xView ArticlePubMedGoogle Scholar
- Calvisi DF, Ladu S, Gorden A, Farina M, Lee JS, Conner EA, Schroeder I, Factor VM, Thorgeirsson SS: Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma. J Clin Invest 2007, 117: 2713–2722. 10.1172/JCI31457View ArticlePubMedPubMed CentralGoogle Scholar
- Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suñer D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu Y-Z, Plass C, Esteller M: Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A 2005, 102: 10604–10609. 10.1073/pnas.0500398102View ArticlePubMedPubMed CentralGoogle Scholar
- Ro¨nn T, Poulsen P, Hansson O, Holmkvist J, Almgren P, Nilsson P, Tuomi T, Isomaa B, Groop L, Vaag A, Ling C: Age influences DNA methylation and gene expression of COX7A1 in human skeletal muscle. Diabetologia 2008, 51: 1159–1168. 10.1007/s00125-008-1018-8View ArticleGoogle Scholar
- Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstråle M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman B, Lander ES, Hirschhorn JN, Altshuler D, Groop LC: PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 2003, 34: 267–273. 10.1038/ng1180View ArticlePubMedGoogle Scholar
- Ling C, Poulsen P, Simonsson S, Ro¨nn T, Holmkvist J, Almgren P, Hagert P, Nilsson E, Mabey AG, Nilsson P, Vaag A, Groop L: Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle. J Clin Invest 2007, 117: 3427–3435. 10.1172/JCI30938View ArticlePubMedPubMed CentralGoogle Scholar
- Caro JF, Triester S, Patel VK, Tapscott EB, Frazier NL, Dohm GL: Liver glucokinase: decreased activity in patients with type II diabetes. Horm Metab Res 1995, 27: 19–22. 10.1055/s-2007-979899View ArticlePubMedGoogle Scholar
- Volkmar M, Dedeurwaerder S, Cunha DA, Ndlovu MN, Defrance M, Deplus R, Calonne E, Volkmar U, Igoillo-Esteve M, Naamane N, Del Guerra S, Masini M, Bugliani M, Marchetti P, Cnop M, Eizirik DL, Fuks F: DNA methylation profiling identifies epigenetic dysregulation in pancreatic islets from type 2 diabetic patients. EMBO J 2012, 31: 1405–1426. 10.1038/emboj.2011.503View ArticlePubMedPubMed CentralGoogle Scholar
- Barski A, Jothi R, Cuddapah S, Cui K, Roh TY, Schones DE, Zhao K: Chromatin poises miRNA- and protein-coding genes for expression. Genome Res 2009, 19: 1742–1751. 10.1101/gr.090951.109View ArticlePubMedPubMed CentralGoogle Scholar
- Heneghan HM, Miller N, Kerin MJ: Role of microRNAs in obesity and the metabolic syndrome. Obes Rev 2010, 11: 354–361. 10.1111/j.1467-789X.2009.00659.xView ArticlePubMedGoogle Scholar
- Poy MN, Eliasson L, Krutzfeldt J, Kuwajima S, Ma X, Macdonald PE, Pfeffer S, Tuschl T, Rajewsky N, Rorsman P, Stoffel M: A pancreatic islet-specific microRNA regulates insulin secretion. Nature 2004, 432: 226–230. 10.1038/nature03076View ArticlePubMedGoogle Scholar
- Poy MN, Spranger M, Stoffel M: microRNAs and the regulation of glucose and lipid metabolism. Diabetes Obes Metab 2007, 9: 67–73. 10.1111/j.1463-1326.2007.00775.xView ArticlePubMedGoogle Scholar
- Papanikolaou V, Iliopoulos D, Dimou I, Dubos S, Tsougos I, Theodorou K, Kitsiou-Tzeli S, Tsezou A: The involvement of HER2 and p53 status in the regulation of telomerase in irradiated breast cancer cells. Int J Oncol 2009, 35: 1141–1149.PubMedGoogle Scholar
- Hamilton JP: Epigenetic mechanisms involved in the pathogenesis of hepatobiliary malignancies. Epigenomics 2010, 2: 233–243. 10.2217/epi.10.9View ArticlePubMedPubMed CentralGoogle Scholar
- Zhao J, Wu G, Bu F, Lu B, Liang A, Cao L, Tong X, Lu X, Wu M, Guo Y: Epigenetic silence of ankyrin-repeat-containing, SH3-domain-containing, and proline-rich-region- containing protein 1 (ASPP1) and ASPP2 genes promotes tumor growth in hepatitis B virus-positive hepatocellular carcinoma. Hepatology 2010, 51: 142–153. 10.1002/hep.23247View ArticlePubMedGoogle Scholar
- Zhang C, Li H, Wang Y, Liu W, Zhang Q, Zhang T, Zhang X, Han B, Zhou G: Epigenetic inactivation of the tumor suppressor gene RIZ1 in hepatocellular carcinoma involves both DNA methylation and histone modifications. J Hepatol 2010, 53: 889–895. 10.1016/j.jhep.2010.05.012View ArticlePubMedGoogle Scholar
- Martin M, Herceg Z: From hepatitis to hepatocellular carcinoma: a proposed model for cross-talk between inflammation and epigenetic mechanisms. Genome Med 2012, 4: 8. 10.1186/gm307View ArticlePubMedPubMed CentralGoogle Scholar
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