Epigenetic Activation of Wnt/β-Catenin Signaling in NAFLD-Associated Hepatocarcinogenesis
Abstract
:1. Epigenetics in NAFLD-HCC
2. Wnt/β-Catenin Signaling and Epigenetics
3. Epigenetic Regulation of Wnt/β-Catenin Signaling in NAFLD-HCC
3.1. DNA Methylation
3.2. Histone Modifications
3.3. MiRNAs
4. Clinical Implications
Acknowledgments
Conflicts of Interest
References
- Villanueva, A.; Hernandez-Gea, V.; Llovet, J.M. Medical therapies for hepatocellular carcinoma: A critical view of the evidence. Nat. Rev. Gastroenterol. Hepatol. 2013, 10, 34–42. [Google Scholar] [CrossRef] [PubMed]
- Makarova-Rusher, O.V.; Altekruse, S.F.; McNeel, T.S.; Ulahannan, S.; Duffy, A.G.; Graubard, B.I.; Greten, T.F.; McGlynn, K.A. Population attributable fractions of risk factors for hepatocellular carcinoma in the united states. Cancer 2016, 122, 1757–1765. [Google Scholar] [CrossRef] [PubMed]
- Bhala, N.; Angulo, P.; van der Poorten, D.; Lee, E.; Hui, J.M.; Saracco, G.; Adams, L.A.; Charatcharoenwitthaya, P.; Topping, J.H.; Bugianesi, E.; et al. The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: An international collaborative study. Hepatology 2011, 54, 1208–1216. [Google Scholar] [CrossRef] [PubMed]
- Farrell, G.C.; van Rooyen, D.; Gan, L.; Chitturi, S. Nash is an inflammatory disorder: Pathogenic, prognostic and therapeutic implications. Gut Liver 2012, 6, 149–171. [Google Scholar] [CrossRef] [PubMed]
- Yuen, M.F.; Tanaka, Y.; Fong, D.Y.; Fung, J.; Wong, D.K.; Yuen, J.C.; But, D.Y.; Chan, A.O.; Wong, B.C.; Mizokami, M.; et al. Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis b. J. Hepatol. 2009, 50, 80–88. [Google Scholar] [CrossRef] [PubMed]
- Wong, V.W.; Chu, W.C.; Wong, G.L.; Chan, R.S.; Chim, A.M.; Ong, A.; Yeung, D.K.; Yiu, K.K.; Chu, S.H.; Woo, J.; et al. Prevalence of non-alcoholic fatty liver disease and advanced fibrosis in hong kong chinese: A population study using proton-magnetic resonance spectroscopy and transient elastography. Gut 2012, 61, 409–415. [Google Scholar] [CrossRef] [PubMed]
- Haladyna, J.N.; Yamauchi, T.; Neff, T.; Bernt, K.M. Epigenetic modifiers in normal and malignant hematopoiesis. Epigenomics 2015, 7, 301–320. [Google Scholar] [CrossRef] [PubMed]
- Dawson, M.A.; Kouzarides, T. Cancer epigenetics: From mechanism to therapy. Cell 2012, 150, 12–27. [Google Scholar] [CrossRef]
- Tsang, D.P.; Wu, W.K.; Kang, W.; Lee, Y.Y.; Wu, F.; Yu, Z.; Xiong, L.; Chan, A.W.; Tong, J.H.; Yang, W.; et al. Yin yang 1-mediated epigenetic silencing of tumour-suppressive micrornas activates nuclear factor-kappab in hepatocellular carcinoma. J. Pathol. 2016, 238, 651–664. [Google Scholar] [CrossRef] [PubMed]
- Tian, Y.; Wong, V.W.; Wong, G.L.; Yang, W.; Sun, H.; Shen, J.; Tong, J.H.; Go, M.Y.; Cheung, Y.S.; Lai, P.B.; et al. Histone deacetylase hdac8 promotes insulin resistance and beta-catenin activation in nafld-associated hepatocellular carcinoma. Cancer Res. 2015, 75, 4803–4816. [Google Scholar] [CrossRef] [PubMed]
- Feng, H.; Yu, Z.; Tian, Y.; Lee, Y.Y.; Li, M.S.; Go, M.Y.; Cheung, Y.S.; Lai, P.B.; Chan, A.M.; To, K.F.; et al. A ccrk-ezh2 epigenetic circuitry drives hepatocarcinogenesis and associates with tumor recurrence and poor survival of patients. J. Hepatol. 2015, 62, 1100–1111. [Google Scholar] [CrossRef] [PubMed]
- Zhang, B.; Chen, J.; Cheng, A.S.; Ko, B.C. Depletion of sirtuin 1 (sirt1) leads to epigenetic modifications of telomerase (tert) gene in hepatocellular carcinoma cells. PLoS ONE 2014, 9, e84931. [Google Scholar] [CrossRef] [PubMed]
- Yip, W.K.; Cheng, A.S.; Zhu, R.; Lung, R.W.; Tsang, D.P.; Lau, S.S.; Chen, Y.; Sung, J.G.; Lai, P.B.; Ng, E.K.; et al. Carboxyl-terminal truncated hbx regulates a distinct microrna transcription program in hepatocellular carcinoma development. PLoS ONE 2011, 6, e22888. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cheng, A.S.; Lau, S.S.; Chen, Y.; Kondo, Y.; Li, M.S.; Feng, H.; Ching, A.K.; Cheung, K.F.; Wong, H.K.; Tong, J.H.; et al. Ezh2-mediated concordant repression of wnt antagonists promotes beta-catenin-dependent hepatocarcinogenesis. Cancer Res. 2011, 71, 4028–4039. [Google Scholar] [CrossRef] [PubMed]
- Tian, Y.; Wong, V.W.; Chan, H.L.; Cheng, A.S. Epigenetic regulation of hepatocellular carcinoma in non-alcoholic fatty liver disease. Semin. Cancer Biol. 2013, 23, 471–482. [Google Scholar] [CrossRef] [PubMed]
- Ahrens, M.; Ammerpohl, O.; von Schonfels, W.; Kolarova, J.; Bens, S.; Itzel, T.; Teufel, A.; Herrmann, A.; Brosch, M.; Hinrichsen, H.; et al. DNA methylation analysis in nonalcoholic fatty liver disease suggests distinct disease-specific and remodeling signatures after bariatric surgery. Cell Metab. 2013, 18, 296–302. [Google Scholar] [CrossRef] [PubMed]
- Pogribny, I.P.; Tryndyak, V.P.; Bagnyukova, T.V.; Melnyk, S.; Montgomery, B.; Ross, S.A.; Latendresse, J.R.; Rusyn, I.; Beland, F.A. Hepatic epigenetic phenotype predetermines individual susceptibility to hepatic steatosis in mice fed a lipogenic methyl-deficient diet. J. Hepatol. 2009, 51, 176–186. [Google Scholar] [CrossRef] [PubMed]
- Ammerpohl, O.; Pratschke, J.; Schafmayer, C.; Haake, A.; Faber, W.; von Kampen, O.; Brosch, M.; Sipos, B.; von Schonfels, W.; Balschun, K.; et al. Distinct DNA methylation patterns in cirrhotic liver and hepatocellular carcinoma. Int. J. Cancer 2012, 130, 1319–1328. [Google Scholar] [CrossRef] [PubMed]
- Drong, A.W.; Lindgren, C.M.; McCarthy, M.I. The genetic and epigenetic basis of type 2 diabetes and obesity. Clin. Pharmacol. Ther. 2012, 92, 707–715. [Google Scholar] [CrossRef] [PubMed]
- Relton, C.L.; Groom, A.; St Pourcain, B.; Sayers, A.E.; Swan, D.C.; Embleton, N.D.; Pearce, M.S.; Ring, S.M.; Northstone, K.; Tobias, J.H.; et al. DNA methylation patterns in cord blood DNA and body size in childhood. PLoS ONE 2012, 7, e31821. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Alenghat, T.; Meyers, K.; Mullican, S.E.; Leitner, K.; Adeniji-Adele, A.; Avila, J.; Bucan, M.; Ahima, R.S.; Kaestner, K.H.; Lazar, M.A. Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology. Nature 2008, 456, 997–1000. [Google Scholar] [CrossRef] [PubMed]
- Feng, D.; Liu, T.; Sun, Z.; Bugge, A.; Mullican, S.E.; Alenghat, T.; Liu, X.S.; Lazar, M.A. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science 2011, 331, 1315–1319. [Google Scholar] [CrossRef] [PubMed]
- Sun, Z.; Miller, R.A.; Patel, R.T.; Chen, J.; Dhir, R.; Wang, H.; Zhang, D.; Graham, M.J.; Unterman, T.G.; Shulman, G.I.; et al. Hepatic HDAC3 promotes gluconeogenesis by repressing lipid synthesis and sequestration. Nat. Med. 2012, 18, 934–942. [Google Scholar] [CrossRef] [PubMed]
- Rottiers, V.; Naar, A.M. Micrornas in metabolism and metabolic disorders. Nat. Rev. Mol. Cell Biol. 2012, 13, 239–250. [Google Scholar] [CrossRef] [PubMed]
- Jordan, S.D.; Kruger, M.; Willmes, D.M.; Redemann, N.; Wunderlich, F.T.; Bronneke, H.S.; Merkwirth, C.; Kashkar, H.; Olkkonen, V.M.; Bottger, T.; et al. Obesity-induced overexpression of mirna-143 inhibits insulin-stimulated akt activation and impairs glucose metabolism. Nat. Cell Biol. 2011, 13, 434–446. [Google Scholar] [CrossRef] [PubMed]
- Rayner, K.J.; Esau, C.C.; Hussain, F.N.; McDaniel, A.L.; Marshall, S.M.; van Gils, J.M.; Ray, T.D.; Sheedy, F.J.; Goedeke, L.; Liu, X.; et al. Inhibition of mir-33a/b in non-human primates raises plasma hdl and lowers VLDL triglycerides. Nature 2011, 478, 404–407. [Google Scholar] [CrossRef] [PubMed]
- Trajkovski, M.; Hausser, J.; Soutschek, J.; Bhat, B.; Akin, A.; Zavolan, M.; Heim, M.H.; Stoffel, M. Micrornas 103 and 107 regulate insulin sensitivity. Nature 2011, 474, 649–653. [Google Scholar] [CrossRef] [PubMed]
- Calin, G.A.; Croce, C.M. Microrna signatures in human cancers. Nat. Rev. Cancer 2006, 6, 857–866. [Google Scholar] [CrossRef] [PubMed]
- Shen, J.; Xiao, Z.; Wu, W.K.; Wang, M.H.; To, K.F.; Chen, Y.; Yang, W.; Li, M.S.; Shin, V.Y.; Tong, J.H.; et al. Epigenetic silencing of mir-490-3p reactivates the chromatin remodeler smarcd1 to promote helicobacter pylori-induced gastric carcinogenesis. Cancer Res. 2015, 75, 754–765. [Google Scholar] [CrossRef] [PubMed]
- Kang, W.; Tong, J.H.; Lung, R.W.; Dong, Y.; Zhao, J.; Liang, Q.; Zhang, L.; Pan, Y.; Yang, W.; Pang, J.C.; et al. Targeting of yap1 by microrna-15a and microrna-16-1 exerts tumor suppressor function in gastric adenocarcinoma. Mol. Cancer 2015. [Google Scholar] [CrossRef] [PubMed]
- Llovet, J.M.; Villanueva, A.; Lachenmayer, A.; Finn, R.S. Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat. Rev. Clin. Oncol. 2015. [Google Scholar] [CrossRef] [PubMed]
- Mok, M.T.; Cheng, A.S. Cul4b: A novel epigenetic driver in wnt/beta-catenin-dependent hepatocarcinogenesis. J. Pathol. 2015, 236, 1–4. [Google Scholar] [CrossRef] [PubMed]
- Yuan, J.; Han, B.; Hu, H.; Qian, Y.; Liu, Z.; Wei, Z.; Liang, X.; Jiang, B.; Shao, C.; Gong, Y. Cul4b activates wnt/beta-catenin signaling in hepatocellular carcinoma by repressing wnt antagonists. J. Pathol. 2015, 135, 784–795. [Google Scholar] [CrossRef] [PubMed]
- Liu, C.; Li, Y.; Semenov, M.; Han, C.; Baeg, G.H.; Tan, Y.; Zhang, Z.; Lin, X.; He, X. Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 2002, 108, 837–847. [Google Scholar] [CrossRef]
- Kimelman, D.; Xu, W. Beta-catenin destruction complex: Insights and questions from a structural perspective. Oncogene 2006, 25, 7482–7491. [Google Scholar] [CrossRef] [PubMed]
- Patil, M.A.; Lee, S.A.; Macias, E.; Lam, E.T.; Xu, C.; Jones, K.D.; Ho, C.; Rodriguez-Puebla, M.; Chen, X. Role of cyclin d1 as a mediator of c-met- and beta-catenin-induced hepatocarcinogenesis. Cancer Res. 2009, 69, 253–261. [Google Scholar] [CrossRef] [PubMed]
- Baylin, S.B.; Ohm, J.E. Epigenetic gene silencing in cancer - a mechanism for early oncogenic pathway addiction? Nat. Rev. Cancer 2006, 6, 107–116. [Google Scholar] [CrossRef] [PubMed]
- Tetsu, O.; McCormick, F. Beta-catenin regulates expression of cyclin d1 in colon carcinoma cells. Nature 1999, 398, 422–426. [Google Scholar] [PubMed]
- Liu, F.; Dong, X.; Lv, H.; Xiu, P.; Li, T.; Wang, F.; Xu, Z.; Li, J. Targeting hypoxia-inducible factor-2alpha enhances sorafenib antitumor activity via beta-catenin/C-myc-dependent pathways in hepatocellular carcinoma. Oncol. Lett. 2015, 10, 778–784. [Google Scholar] [PubMed]
- Ying, Y.; Tao, Q. Epigenetic disruption of the Wnt/beta-catenin signaling pathway in human cancers. Epigenetics 2009, 4, 307–312. [Google Scholar] [CrossRef] [PubMed]
- MacDonald, B.T.; Tamai, K.; He, X. Wnt/beta-catenin signaling: Components, mechanisms, and diseases. Dev. Cell 2009, 17, 9–26. [Google Scholar] [CrossRef] [PubMed]
- Barker, N.; Clevers, H. Mining the Wnt pathway for cancer therapeutics. Nat. Rev. Drug Discov. 2006, 5, 997–1014. [Google Scholar] [CrossRef] [PubMed]
- Cui, J.; Zhou, X.; Liu, Y.; Tang, Z.; Romeih, M. Wnt signaling in hepatocellular carcinoma: Analysis of mutation and expression of beta-catenin, t-cell factor-4 and glycogen synthase kinase 3-beta genes. J. Gastroenterol. Hepatol. 2003, 18, 280–287. [Google Scholar] [CrossRef] [PubMed]
- Ishizaki, Y.; Ikeda, S.; Fujimori, M.; Shimizu, Y.; Kurihara, T.; Itamoto, T.; Kikuchi, A.; Okajima, M.; Asahara, T. Immunohistochemical analysis and mutational analyses of beta-catenin, axin family and apc genes in hepatocellular carcinomas. Int. J. Oncol. 2004, 24, 1077–1083. [Google Scholar] [PubMed]
- Chan, D.W.; Chan, C.Y.; Yam, J.W.; Ching, Y.P.; Ng, I.O. Prickle-1 negatively regulates Wnt/beta-catenin pathway by promoting dishevelled ubiquitination/degradation in liver cancer. Gastroenterology 2006, 131, 1218–1227. [Google Scholar] [CrossRef] [PubMed]
- Murphy, S.K.; Yang, H.; Moylan, C.A.; Pang, H.; Dellinger, A.; Abdelmalek, M.F.; Garrett, M.E.; Ashley-Koch, A.; Suzuki, A.; Tillmann, H.L.; et al. Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease. Gastroenterology 2013, 145, 1076–1087. [Google Scholar] [CrossRef] [PubMed]
- Kawano, Y.; Kypta, R. Secreted antagonists of the wnt signalling pathway. J. Cell Sci. 2003, 116, 2627–2634. [Google Scholar] [CrossRef] [PubMed]
- Kaur, P.; Mani, S.; Cros, M.P.; Scoazec, J.Y.; Chemin, I.; Hainaut, P.; Herceg, Z. Epigenetic silencing of sfrp1 activates the canonical Wnt pathway and contributes to increased cell growth and proliferation in hepatocellular carcinoma. Tumour Biol. 2012, 33, 325–336. [Google Scholar] [CrossRef] [PubMed]
- Takagi, H.; Sasaki, S.; Suzuki, H.; Toyota, M.; Maruyama, R.; Nojima, M.; Yamamoto, H.; Omata, M.; Tokino, T.; Imai, K.; et al. Frequent epigenetic inactivation of SFRP genes in hepatocellular carcinoma. J. Gastroenterol. 2008, 43, 378–389. [Google Scholar] [CrossRef] [PubMed]
- Gutierrez-Vidal, R.; Vega-Badillo, J.; Reyes-Fermin, L.M.; Hernandez-Perez, H.A.; Sanchez-Munoz, F.; Lopez-Alvarez, G.S.; Larrieta-Carrasco, E.; Fernandez-Silva, I.; Mendez-Sanchez, N.; Tovar, A.R.; et al. SFRP5 hepatic expression is associated with non-alcoholic liver disease in morbidly obese women. Ann. Hepatol. 2015, 14, 666–674. [Google Scholar] [PubMed]
- Jia, Y.; Yang, Y.; Liu, S.; Herman, J.G.; Lu, F.; Guo, M. Sox17 antagonizes Wnt/beta-catenin signaling pathway in hepatocellular carcinoma. Epigenetics 2010, 5, 743–749. [Google Scholar] [CrossRef] [PubMed]
- Jonatan, D.; Spence, J.R.; Method, A.M.; Kofron, M.; Sinagoga, K.; Haataja, L.; Arvan, P.; Deutsch, G.H.; Wells, J.M. Sox17 regulates insulin secretion in the normal and pathologic mouse beta cell. PLoS ONE 2014, 9, e104675. [Google Scholar] [CrossRef] [PubMed]
- Chettouh, H.; Lequoy, M.; Fartoux, L.; Vigouroux, C.; Desbois-Mouthon, C. Hyperinsulinaemia and insulin signalling in the pathogenesis and the clinical course of hepatocellular carcinoma. Liver Int. 2015, 35, 2203–2217. [Google Scholar] [CrossRef] [PubMed]
- Cheyette, B.N.; Waxman, J.S.; Miller, J.R.; Takemaru, K.; Sheldahl, L.C.; Khlebtsova, N.; Fox, E.P.; Earnest, T.; Moon, R.T. Dapper, a dishevelled-associated antagonist of beta-catenin and JNK signaling, is required for notochord formation. Dev. Cell 2002, 2, 449–461. [Google Scholar] [CrossRef]
- Zhang, X.; Yang, Y.; Liu, X.; Herman, J.G.; Brock, M.V.; Licchesi, J.D.; Yue, W.; Pei, X.; Guo, M. Epigenetic regulation of the Wnt signaling inhibitor DACT2 in human hepatocellular carcinoma. Epigenetics 2013, 8, 373–382. [Google Scholar] [CrossRef] [PubMed]
- Jiang, X.; Tan, J.; Li, J.; Kivimae, S.; Yang, X.; Zhuang, L.; Lee, P.L.; Chan, M.T.; Stanton, L.W.; Liu, E.T.; et al. DACT3 is an epigenetic regulator of Wnt/beta-catenin signaling in colorectal cancer and is a therapeutic target of histone modifications. Cancer Cell 2008, 13, 529–541. [Google Scholar] [CrossRef] [PubMed]
- Kondo, Y.; Shen, L.; Cheng, A.S.; Ahmed, S.; Boumber, Y.; Charo, C.; Yamochi, T.; Urano, T.; Furukawa, K.; Kwabi-Addo, B.; et al. Gene silencing in cancer by histone h3 lysine 27 trimethylation independent of promoter DNA methylation. Nature Genet. 2008, 40, 741–750. [Google Scholar] [CrossRef] [PubMed]
- Wang, L.; Jin, Q.; Lee, J.E.; Su, I.H.; Ge, K. Histone H3K27 methyltransferase Ezh2 represses Wnt genes to facilitate adipogenesis. Proc. Natl. Acad. Sci. USA 2010, 107, 7317–7322. [Google Scholar] [CrossRef] [PubMed]
- Galmozzi, A.; Mitro, N.; Ferrari, A.; Gers, E.; Gilardi, F.; Godio, C.; Cermenati, G.; Gualerzi, A.; Donetti, E.; Rotili, D.; et al. Inhibition of class I histone deacetylases unveils a mitochondrial signature and enhances oxidative metabolism in skeletal muscle and adipose tissue. Diabetes 2013, 62, 732–742. [Google Scholar] [CrossRef] [PubMed]
- Liu, X.Y.; Xu, J.F. Reduced histone H3 acetylation in CD4(+) t lymphocytes: Potential mechanism of latent autoimmune diabetes in adults. Dis. Markers 2015. [Google Scholar] [CrossRef] [PubMed]
- Yu, Z.; Cheng, A.S. Epigenetic deregulation of micrornas: New opportunities to target oncogenic signaling pathways in hepatocellular carcinoma. Curr. Pharm. Des. 2013, 19, 1192–1200. [Google Scholar] [PubMed]
- Tessitore, A.; Cicciarelli, G.; Del Vecchio, F.; Gaggiano, A.; Verzella, D.; Fischietti, M.; Mastroiaco, V.; Vetuschi, A.; Sferra, R.; Barnabei, R.; et al. Microrna expression analysis in high fat diet-induced nafld-nash-hcc progression: Study on C57BL/6J mice. BMC Cancer 2016. [Google Scholar] [CrossRef] [PubMed]
- Xu, J.; Zhu, X.; Wu, L.; Yang, R.; Yang, Z.; Wang, Q.; Wu, F. Microrna-122 suppresses cell proliferation and induces cell apoptosis in hepatocellular carcinoma by directly targeting Wnt/beta-catenin pathway. Liver Int. 2012, 32, 752–760. [Google Scholar] [CrossRef] [PubMed]
- Bandiera, S.; Pfeffer, S.; Baumert, T.F.; Zeisel, M.B. Mir-122––A key factor and therapeutic target in liver disease. J. Hepatol. 2015, 62, 448–457. [Google Scholar] [CrossRef] [PubMed]
- Hsu, S.H.; Wang, B.; Kota, J.; Yu, J.; Costinean, S.; Kutay, H.; Yu, L.; Bai, S.; La Perle, K.; Chivukula, R.R.; et al. Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of mir-122 in liver. J. Clin. Invest. 2012, 122, 2871–2883. [Google Scholar] [CrossRef] [PubMed]
- Liang, T.; Liu, C.; Ye, Z. Deep sequencing of small rna repertoires in mice reveals metabolic disorders-associated hepatic mirnas. PLoS ONE 2013, 8, e80774. [Google Scholar] [CrossRef] [PubMed]
- Iliopoulos, D.; Drosatos, K.; Hiyama, Y.; Goldberg, I.J.; Zannis, V.I. MicroRNA-370 controls the expression of microRNA-122 and CPT1alpha and affects lipid metabolism. J. Lipid Res. 2010, 51, 1513–1523. [Google Scholar] [CrossRef] [PubMed]
- Esau, C.; Davis, S.; Murray, S.F.; Yu, X.X.; Pandey, S.K.; Pear, M.; Watts, L.; Booten, S.L.; Graham, M.; McKay, R.; et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab. 2006, 3, 87–98. [Google Scholar] [CrossRef] [PubMed]
- Sun, F.; Fu, H.; Liu, Q.; Tie, Y.; Zhu, J.; Xing, R.; Sun, Z.; Zheng, X. Downregulation of ccnd1 and CDK6 by miR-34a induces cell cycle arrest. FEBS Lett. 2008, 582, 1564–1568. [Google Scholar] [CrossRef] [PubMed]
- Cheng, J.; Zhou, L.; Xie, Q.F.; Xie, H.Y.; Wei, X.Y.; Gao, F.; Xing, C.Y.; Xu, X.; Li, L.J.; Zheng, S.S. The impact of miR-34a on protein output in hepatocellular carcinoma HepG2 cells. Proteomics 2010, 10, 1557–1572. [Google Scholar] [CrossRef] [PubMed]
- Gougelet, A.; Sartor, C.; Bachelot, L.; Godard, C.; Marchiol, C.; Renault, G.; Tores, F.; Nitschke, P.; Cavard, C.; Terris, B.; et al. Antitumour activity of an inhibitor of miR-34a in liver cancer with beta-catenin-mutations. Gut 2015, 65, 1024–1034. [Google Scholar] [CrossRef] [PubMed]
- Afonso, M.B.; Rodrigues, P.M.; Simao, A.L.; Castro, R.E. Circulating micrornas as potential biomarkers in non-alcoholic fatty liver disease and hepatocellular carcinoma. J. Clin. Med. 2016. [Google Scholar] [CrossRef] [PubMed]
- Wen, F.; Yang, Y.; Jin, D.; Sun, J.; Yu, X.; Yang, Z. miRNA-145 is involved in the development of resistin-induced insulin resistance in HepG2 cells. Biochem. Biophys. Res. Commun. 2014, 445, 517–523. [Google Scholar] [CrossRef] [PubMed]
- Jin, X.; Chen, Y.P.; Kong, M.; Zheng, L.; Yang, Y.D.; Li, Y.M. Transition from hepatic steatosis to steatohepatitis: Unique microRNA patterns and potential downstream functions and pathways. J. Gastroenterol. Hepatol. 2012, 27, 331–340. [Google Scholar] [CrossRef] [PubMed]
- Xia, H.; Ooi, L.L.; Hui, K.M. miR-214 targets beta-catenin pathway to suppress invasion, stem-like traits and recurrence of human hepatocellular carcinoma. PLoS ONE 2012, 7, e44206. [Google Scholar]
- Oronsky, B.; Oronsky, N.; Knox, S.; Fanger, G.; Scicinski, J. Episensitization: Therapeutic tumor resensitization by epigenetic agents: A review and reassessment. Anticancer Agents Med. Chem. 2014, 14, 1121–1127. [Google Scholar] [CrossRef] [PubMed]
- Lin, Y.W.; Shih, Y.L.; Lien, G.S.; Suk, F.M.; Hsieh, C.B.; Yan, M.D. Promoter methylation of SFRP3 is frequent in hepatocellular carcinoma. Dis. Markers 2014. [Google Scholar] [CrossRef] [PubMed]
- Yoshikawa, H.; Matsubara, K.; Zhou, X.; Okamura, S.; Kubo, T.; Murase, Y.; Shikauchi, Y.; Esteller, M.; Herman, J.G.; Wei Wang, X.; et al. Wnt10b functional dualism: Beta-catenin/TCF-dependent growth promotion or independent suppression with deregulated expression in cancer. Mol. Biol. Cell 2007, 18, 4292–4303. [Google Scholar] [CrossRef] [PubMed]
- Quan, H.; Zhou, F.; Nie, D.; Chen, Q.; Cai, X.; Shan, X.; Zhou, Z.; Chen, K.; Huang, A.; Li, S.; et al. Hepatitis C virus core protein epigenetically silences SFRP1 and enhances HCC aggressiveness by inducing epithelial-mesenchymal transition. Oncogene 2014, 33, 2826–2835. [Google Scholar] [CrossRef] [PubMed]
- George, J.; Patel, T. Noncoding rna as therapeutic targets for hepatocellular carcinoma. Semin. Liver Dis. 2015, 35, 63–74. [Google Scholar] [CrossRef] [PubMed]
Epigenetic Regulation | Gene Name | Epigenetic Changes | Roles in Wnt/β-Catenin | Roles in NAFLD | Roles in HCC | References |
---|---|---|---|---|---|---|
DNA methylation | SFRP5 | Hypermethylation | Prevent ligand-receptor interactions | Down-regulated in obese people with non-alcoholic liver disease | Down-regulated in HCC patients | [46,47,48] |
SOX17 | Hypermethylation | Interact with the nuclear transcription complex TCF/LEF | Regulate insulin secretion in mice | Down-regulated in HCC patients | [51,52] | |
DACT2 | Hypermethylation | Antagonize Dvl | Hypermethylated promoter in advanced NAFLD patients | Down-regulated in HCC patients | [54,55] | |
Histone modification | EZH2 | H3K27 trimethylation | Suppress AXIN2, NKD1, PPP2R2B, PRICKLE1 and SFRP5 | Up-regulated in NAFLD-HCC patients and mouse model | Up-regulated in HCC patients | [10,14,58] |
HDAC1 | Interaction with EZH2 | Suppress AXIN2, NKD1, PPP2R2B, PRICKLE1 and SFRP5 | Class I selective HDAC inhibitor reduces body weight, and glucose and insulin levels in mice | Up-regulated in HCC patients | [14,59,60] | |
HDAC8 | Interaction with EZH2, H4 acetylation | Suppress AXIN2, NKD1, PPP2R2B and PRICKLE1 | Up-regulated in NAFLD-HCC patients and mouse model | Up-regulated in NAFLD-HCC patients | [10] | |
MicroRNAs | miR-122 | Down-regulation | Suppress Wnt1 activity | Increased fatty acid oxidation rates and reduced fatty acid synthesis | Down-regulated in HCC patients | [63,64,65,66,67,68] |
miR-34a | Down-regulation | Induce cyclin D1 expression | Increased at serum levels in NAFLD patients | Down-regulated in HCC patients | [69,70,71,72] | |
miR-145 | Down-regulation | Reduce β-catenin levels | Down-regulated in mouse model | Down-regulated in HCC patients | [73,74] |
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Tian, Y.; Mok, M.T.S.; Yang, P.; Cheng, A.S.L. Epigenetic Activation of Wnt/β-Catenin Signaling in NAFLD-Associated Hepatocarcinogenesis. Cancers 2016, 8, 76. https://doi.org/10.3390/cancers8080076
Tian Y, Mok MTS, Yang P, Cheng ASL. Epigenetic Activation of Wnt/β-Catenin Signaling in NAFLD-Associated Hepatocarcinogenesis. Cancers. 2016; 8(8):76. https://doi.org/10.3390/cancers8080076
Chicago/Turabian StyleTian, Yuan, Myth T.S. Mok, Pengyuan Yang, and Alfred S.L. Cheng. 2016. "Epigenetic Activation of Wnt/β-Catenin Signaling in NAFLD-Associated Hepatocarcinogenesis" Cancers 8, no. 8: 76. https://doi.org/10.3390/cancers8080076