{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T03:42:31Z","timestamp":1782963751055,"version":"3.54.5"},"reference-count":143,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2018,6,5]],"date-time":"2018-06-05T00:00:00Z","timestamp":1528156800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Chronic viral hepatitis is a global public health problem, with approximately 570 million persons chronically infected. Hepatitis B and C viruses increase the risk of morbidity and mortality from liver cirrhosis, hepatocellular carcinoma (HCC), and extrahepatic complications that develop. Hepatitis virus infection induces transforming growth factor (TGF)-\u03b2, which influences microenvironments within the infected liver. TGF-\u03b2 promotes liver fibrosis by up-regulating extracellular matrix production by hepatic stellate cells. TGF-\u03b2 is also up-regulated in patients with HCC, in whom it contributes importantly to bringing about a favorable microenvironment for tumor growth. Thus, TGF-\u03b2 is thought to be a major factor regulating liver fibrosis and carcinogenesis. Since TGF-\u03b2 carries out regulatory signaling by influencing the phosphorylation of Smads, we have generated several kinds of phospho-specific antibodies to Smad2\/3. Using these, we have identified three types of phospohorylated forms: COOH-terminally phosphorylated Smad2\/3 (pSmad2C and pSmad3C), linker phosphorylated Smad2\/3 (pSmad2L and pSmad3L), and dually phosphorylated Smad3 (pSmad2L\/C and pSmad3L\/C). TGF-\u03b2-mediated pSmad2\/3C signaling terminates cell proliferation; on the other hand, cytokine-induced pSmad3L signaling accelerates cell proliferation and promotes fibrogenesis. This review addresses TGF-\u03b2\/Smad signal transduction in chronic liver injuries and carcinogenic processes. We also discuss the reversibility of Smad signaling after antiviral therapy.<\/jats:p>","DOI":"10.3390\/cancers10060183","type":"journal-article","created":{"date-parts":[[2018,6,5]],"date-time":"2018-06-05T11:04:46Z","timestamp":1528196686000},"page":"183","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Clinico-Pathological Importance of TGF-\u03b2\/Phospho-Smad Signaling during Human Hepatic Fibrocarcinogenesis"],"prefix":"10.3390","volume":"10","author":[{"given":"Katsunori","family":"Yoshida","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Kansai Medical University 2-5-1, Shin-Machi, Hirakata, Osaka 573-1010, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Matsuzaki","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Kansai Medical University 2-5-1, Shin-Machi, Hirakata, Osaka 573-1010, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miki","family":"Murata","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Kansai Medical University 2-5-1, Shin-Machi, Hirakata, Osaka 573-1010, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Kansai Medical University 2-5-1, Shin-Machi, Hirakata, Osaka 573-1010, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanehiko","family":"Suwa","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Kansai Medical University 2-5-1, Shin-Machi, Hirakata, Osaka 573-1010, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuichi","family":"Okazaki","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Kansai Medical University 2-5-1, Shin-Machi, Hirakata, Osaka 573-1010, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,6,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Dooley, J.S., Lok, A.F., Burroughs, A.K., and Heathcote, E.J. (2011). Sherlock's Disease of the Liver and Biliary System, Wiley-Blackwell.","DOI":"10.1002\/9781444341294"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"174","DOI":"10.7326\/0003-4819-131-3-199908030-00003","article-title":"Interferon therapy reduces the risk for hepatocellular carcinoma: National surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. IHIT Study Group. Inhibition of Hepatocarcinogenesis by Interferon Therapy","volume":"131","author":"Yoshida","year":"1999","journal-title":"Ann. Intern. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.jhep.2007.11.011","article-title":"Natural history of chronic hepatitis B: Special emphasis on disease progression and prognostic factors","volume":"48","author":"Fattovich","year":"2008","journal-title":"J. hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1136\/gut.2005.088690","article-title":"Emerging insights into Transforming growth factor beta Smad signal in hepatic fibrogenesis","volume":"56","author":"Inagaki","year":"2007","journal-title":"Gut"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1007\/s00441-011-1246-y","article-title":"TGF-beta in progression of liver disease","volume":"347","author":"Dooley","year":"2012","journal-title":"Cell Tissue Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/S0959-437X(96)80087-6","article-title":"Regulation of differentiation by TGF-beta","volume":"6","author":"Moses","year":"1996","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_7","unstructured":"Rovberts, A.B., and Seyedin, M. (1990). The Transforming Growth Factor-bs, Springer."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/978-1-4419-6033-7_5","article-title":"Tgf-beta signaling alterations and colon cancer","volume":"155","author":"Bellam","year":"2010","journal-title":"Cancer Treat. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1093\/carcin\/bgr172","article-title":"Smad phosphoisoform signaling specificity: The right place at the right time","volume":"32","author":"Matsuzaki","year":"2011","journal-title":"Carcinogenesis"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s00441-011-1178-6","article-title":"Smad phosphoisoform signals in acute and chronic liver injury: Similarities and differences between epithelial and mesenchymal cells","volume":"347","author":"Matsuzaki","year":"2012","journal-title":"Cell Tissue Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.cytogfr.2013.06.002","article-title":"Smad phospho-isoforms direct context-dependent TGF-beta signaling","volume":"24","author":"Matsuzaki","year":"2013","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/37284","article-title":"TGF-beta signalling from cell membrane to nucleus through SMAD proteins","volume":"390","author":"Heldin","year":"1997","journal-title":"Nature"},{"key":"ref_13","unstructured":"Derynck, R., and Miyazono, K. (2008). The TGF-b Signaling, Cold Spring Harbor Laboratory Press."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/cr.2008.302","article-title":"Signaling cross-talk between TGF-beta\/BMP and other pathways","volume":"19","author":"Guo","year":"2009","journal-title":"Cell Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1016\/S0092-8674(00)80303-7","article-title":"The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling","volume":"89","author":"Hayashi","year":"1997","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1038\/39369","article-title":"Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signaling","volume":"389","author":"Nakao","year":"1997","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"19808","DOI":"10.1074\/jbc.M109.016667","article-title":"A negative feedback control of transforming growth factor-beta signaling by glycogen synthase kinase 3-mediated Smad3 linker phosphorylation at Ser-204","volume":"284","author":"Millet","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1038\/nrm3434","article-title":"TGF\u03b2 signalling in context","volume":"13","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.cytogfr.2005.09.010","article-title":"Smad3 phosphorylation by cyclin-dependent kinases","volume":"17","author":"Liu","year":"2006","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/cr.2008.327","article-title":"Phospho-control of TGF-beta superfamily signaling","volume":"19","author":"Wrighton","year":"2009","journal-title":"Cell Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1101\/gad.13.7.804","article-title":"A mechanism of repression of TGFbeta\/Smad signaling by oncogenic Ras","volume":"13","author":"Kretzschmar","year":"1999","journal-title":"Genes Dev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1038\/nature02650","article-title":"Cyclin-dependent kinases regulate the antiproliferative function of Smads","volume":"430","author":"Matsuura","year":"2004","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5090","DOI":"10.1158\/0008-5472.CAN-06-4629","article-title":"Reversible Smad-dependent signaling between tumor suppression and oncogenesis","volume":"67","author":"Sekimoto","year":"2007","journal-title":"Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5321","DOI":"10.1158\/0008-5472.CAN-08-4203","article-title":"Smad2 and Smad3 phosphorylated at both linker and COOH-terminal regions transmit malignant TGF-beta signal in later stages of human colorectal cancer","volume":"69","author":"Matsuzaki","year":"2009","journal-title":"Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/j.cell.2009.09.035","article-title":"Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways","volume":"139","author":"Alarcon","year":"2009","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7416","DOI":"10.1038\/sj.onc.1207981","article-title":"TGF-beta and HGF transmit the signals through JNK-dependent Smad2\/3 phosphorylation at the linker regions","volume":"23","author":"Mori","year":"2004","journal-title":"Oncogene"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1002\/hep.21672","article-title":"Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor beta signaling, promoting cirrhosis and hepatocellular carcinoma","volume":"46","author":"Matsuzaki","year":"2007","journal-title":"Hepatology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.molcel.2009.09.043","article-title":"Ubiquitin ligase Nedd4L targets activated Smad2\/3 to limit TGF-beta signaling","volume":"36","author":"Gao","year":"2009","journal-title":"Mol. Cell."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"13467","DOI":"10.1074\/jbc.M112.431775","article-title":"TGF-beta-activated kinase 1 (Tak1) mediates agonist-induced Smad activation and linker region phosphorylation in embryonic craniofacial neural crest-derived cells","volume":"288","author":"Yumoto","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5178","DOI":"10.1093\/emboj\/19.19.5178","article-title":"Smad2, Smad3 and Smad4 cooperate with Sp1 to induce p15(Ink4B) transcription in response to TGF-beta","volume":"19","author":"Feng","year":"2000","journal-title":"EMBO J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"29244","DOI":"10.1074\/jbc.M909467199","article-title":"Role of Smad proteins and transcription factor Sp1 in p21(Waf1\/Cip1) regulation by transforming growth factor-beta","volume":"275","author":"Pardali","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2546","DOI":"10.1128\/MCB.24.6.2546-2559.2004","article-title":"Transforming growth factor beta-mediated transcriptional repression of c-myc is dependent on direct binding of Smad3 to a novel repressive Smad binding element","volume":"24","author":"Frederick","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/j.ccr.2006.04.025","article-title":"Smad3 reduces susceptibility to hepatocarcinoma by sensitizing hepatocytes to apoptosis through downregulation of Bcl-2","volume":"9","author":"Yang","year":"2006","journal-title":"Cancer Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/S0092-8674(00)00116-1","article-title":"Signal transduction by the JNK group of MAP kinases","volume":"103","author":"Davis","year":"2000","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/nrc2694","article-title":"Signal integration by JNK and p38 MAPK pathways in cancer development","volume":"9","author":"Wagner","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/S0092-8674(00)81556-1","article-title":"Regulation of Smad activity","volume":"100","author":"Wrana","year":"2000","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1038\/31593","article-title":"SMAD proteins and mammalian anatomy","volume":"393","author":"Derynck","year":"1998","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1146\/annurev.cellbio.21.022404.142018","article-title":"Specificity and versatility in TGF-beta signaling through Smads","volume":"21","author":"Feng","year":"2005","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"13909","DOI":"10.1073\/pnas.0506517102","article-title":"Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway","volume":"102","author":"Kang","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1002\/hep.1840380414","article-title":"p38 MAPK mediates fibrogenic signal through Smad3 phosphorylation in rat myofibroblasts","volume":"38","author":"Furukawa","year":"2003","journal-title":"Hepatology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/S0165-2478(02)00023-8","article-title":"Mechanisms of TGF-beta signaling in regulation of cell growth and differentiation","volume":"82","author":"Moustakas","year":"2002","journal-title":"Immunol. Lett."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3943","DOI":"10.1172\/JCI37156","article-title":"Proliferation of human HCC cells and chemically induced mouse liver cancers requires JNK1-dependent p21 downregulation","volume":"118","author":"Hui","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1002\/hep.22765","article-title":"Hepatitis B virus X protein shifts human hepatic transforming growth factor (TGF)-beta signaling from tumor suppression to oncogenesis in early chronic hepatitis B","volume":"49","author":"Murata","year":"2009","journal-title":"Hepatology"},{"key":"ref_44","first-page":"3645","article-title":"Transforming growth factor beta 1 suppresses genomic instability independent of a G1 arrest. p53, and Rb","volume":"56","author":"Glick","year":"1996","journal-title":"Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1038\/sj.onc.1203471","article-title":"Defects in TGF-beta signaling overcome senescence of mouse keratinocytes expressing v-Ha-ras","volume":"19","author":"Tremain","year":"2000","journal-title":"Oncogene"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"6264","DOI":"10.1073\/pnas.80.20.6264","article-title":"Sarcoma growth factor from conditioned medium of virally transformed cells is composed of both type alpha and type beta transforming growth factors","volume":"80","author":"Anzano","year":"1983","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"8797","DOI":"10.1074\/jbc.274.13.8797","article-title":"MEKK-1, a component of the stress (stress-activated protein kinase\/c-Jun N-terminal kinase) pathway, can selectively activate Smad2-mediated transcriptional activation in endothelial cells","volume":"274","author":"Brown","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1158\/1541-7786.MCR-09-0537","article-title":"Cyclin-dependent kinase 4-mediated phosphorylation inhibits Smad3 activity in cyclin D-overexpressing breast cancer cells","volume":"8","author":"Zelivianski","year":"2010","journal-title":"Mol. Cancer Res. MCR"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4900","DOI":"10.4161\/cc.9.24.14158","article-title":"Impact of cyclin E overexpression on Smad3 activity in breast cancer cell lines","volume":"9","author":"Cooley","year":"2010","journal-title":"Cell Cycle"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1038\/35082500","article-title":"Specific protection against breast cancers by cyclin D1 ablation","volume":"411","author":"Yu","year":"2001","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/sj.onc.1201171","article-title":"Mutual requirement of CDK4 and Myc in malignant transformation: Evidence for cyclin D1\/CDK4 and p16INK4A as upstream regulators of Myc","volume":"15","author":"Haas","year":"1997","journal-title":"Oncogene"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1074\/jbc.M109.063826","article-title":"Pin1 promotes transforming growth factor-beta-induced migration and invasion","volume":"285","author":"Matsuura","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Hirschhorn, T., Barizilay, L., Smorodinsky, N.I., and Ehrlich, M. (2012). Differential regulation of Smad3 and of the type II transforming growth factor-beta receptor in mitosis: Implications for signaling. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0043459"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/S0016-5085(03)00666-8","article-title":"Smad7 prevents activation of hepatic stellate cells and liver fibrosis in rats","volume":"125","author":"Dooley","year":"2003","journal-title":"Gastroenterology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1002\/hep.22934","article-title":"The etiology of liver damage imparts cytokines transforming growth factor beta1 or interleukin-13 as driving forces in fibrogenesis","volume":"50","author":"Weng","year":"2009","journal-title":"Hepatology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1586\/egh.10.47","article-title":"Update on the pathophysiology of liver fibrosis","volume":"4","author":"Pinzani","year":"2010","journal-title":"Expert Rev. Gastroenterol. Hepatol."},{"key":"ref_57","first-page":"760","article-title":"Transforming growth factor-beta 1 (TGF-beta 1) and TGF-beta 1 receptors in normal, cirrhotic, and neoplastic human livers","volume":"21","author":"Bedossa","year":"1995","journal-title":"Hepatology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1172\/JCI118055","article-title":"Cell-specific expression of transforming growth factor-beta in rat liver. Evidence for autocrine regulation of hepatocyte proliferation","volume":"96","author":"Bissell","year":"1995","journal-title":"J. Clin. Investig."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/0304-3835(95)90156-6","article-title":"Positive correlation of plasma transforming growth factor-beta 1 levels with tumor vascularity in hepatocellular carcinoma","volume":"89","author":"Ito","year":"1995","journal-title":"Cancer Lett."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2275","DOI":"10.1002\/1097-0142(19940501)73:9<2275::AID-CNCR2820730907>3.0.CO;2-T","article-title":"Plasma transforming growth factor-beta 1 in patients with hepatocellular carcinoma. Comparison with chronic liver diseases","volume":"73","author":"Shirai","year":"1994","journal-title":"Cancer"},{"key":"ref_61","first-page":"127","article-title":"Mutation analysis of transforming growth factor beta type II receptor, Smad2, and Smad4 in hepatocellular carcinoma","volume":"14","author":"Kawate","year":"1999","journal-title":"Int. J. Oncol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"4879","DOI":"10.1038\/sj.onc.1202866","article-title":"Smad2 and Smad4 gene mutations in hepatocellular carcinoma","volume":"18","author":"Yakicier","year":"1999","journal-title":"Oncogene"},{"key":"ref_63","first-page":"49","article-title":"Mutational analysis of the Smad6 and Smad7 genes in hepatocellular carcinoma","volume":"8","author":"Kawate","year":"2001","journal-title":"Int. J. Mol. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.cytogfr.2005.09.009","article-title":"Alterations in components of the TGF-beta superfamily signaling pathways in human cancer","volume":"17","author":"Levy","year":"2006","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1002\/(SICI)1097-0215(19990611)81:6<851::AID-IJC2>3.0.CO;2-D","article-title":"Gene mutation of transforming growth factor beta1 type II receptor in hepatocellular carcinoma","volume":"81","author":"Furuta","year":"1999","journal-title":"Int. J. Cancer"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1101\/gr.133926.111","article-title":"The effects of hepatitis B virus integration into the genomes of hepatocellular carcinoma patients","volume":"22","author":"Jiang","year":"2012","journal-title":"Genome Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1056\/NEJM198110293051807","article-title":"Integration of hepatitis B virus DNA into the genome of liver cells in chronic liver disease and hepatocellular carcinoma. Studies in percutaneous liver biopsies and post-mortem tissue specimens","volume":"305","author":"Shafritz","year":"1981","journal-title":"N. Engl. J. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1016\/j.jhep.2005.02.005","article-title":"The role of hepatitis B virus integrations in the pathogenesis of human hepatocellular carcinoma","volume":"42","author":"Roberts","year":"2005","journal-title":"J. Hepatol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/sj.onc.1200850","article-title":"The hepatitis B virus X gene potentiates c-Myc-induced liver oncogenesis in transgenic mice","volume":"14","author":"Terradillos","year":"1997","journal-title":"Oncogene"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.canlet.2006.11.010","article-title":"Hepatitis B virus integration, fragile sites, and hepatocarcinogenesis","volume":"252","author":"Feitelson","year":"2007","journal-title":"Cancer Lett."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1016\/j.humpath.2004.09.012","article-title":"c-Myc overexpression in hepatocarcinogenesis","volume":"35","author":"Feitelson","year":"2004","journal-title":"Hum. Pathol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1002\/hep.1840190403","article-title":"High-level expression of hepatitis B virus HBx gene and hepatocarcinogenesis in transgenic mice","volume":"19","author":"Koike","year":"1994","journal-title":"Hepatology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1053\/jhep.2000.19343","article-title":"Hepatitis C virus core protein activates the MAPK\/ERK cascade synergistically with tumor promoter TPA, but not with epidermal growth factor or transforming growth factor alpha","volume":"32","author":"Hayashi","year":"2000","journal-title":"Hepatology"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1006\/viro.2001.1227","article-title":"Hepatitis C virus core protein induces cell proliferation and activates ERK, JNK, and p38 MAP kinases together with the MAP kinase phosphatase MKP-1 in a HepG2 Tet-Off cell line","volume":"292","author":"Erhardt","year":"2002","journal-title":"Virology"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"9207","DOI":"10.1128\/JVI.76.18.9207-9217.2002","article-title":"Subversion of cell signaling pathways by hepatitis C virus nonstructural 5A protein via interaction with Grb2 and P85 phosphatidylinositol 3-kinase","volume":"76","author":"He","year":"2002","journal-title":"J. Virol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1042\/bj20031587","article-title":"Induced oxidative stress and activated expression of manganese superoxide dismutase during hepatitis C virus replication: Role of JNK, p38 MAPK and AP-1","volume":"378","author":"Qadri","year":"2004","journal-title":"Biochem. J."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.yexcr.2004.12.024","article-title":"Hepatitis C virus E2 protein promotes human hepatoma cell proliferation through the MAPK\/ERK signaling pathway via cellular receptors","volume":"305","author":"Zhao","year":"2005","journal-title":"Exp. Cell Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.virol.2005.01.008","article-title":"Activation of c-Jun NH2-terminal kinase (JNK) signaling pathway is essential for the stimulation of hepatitis C virus (HCV) non-structural protein 3 (NS3)-mediated cell growth","volume":"333","author":"Hassan","year":"2005","journal-title":"Virology"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"7468","DOI":"10.1074\/jbc.M512438200","article-title":"Modulation of the transforming growth factor-beta signal transduction pathway by hepatitis C virus nonstructural 5A protein","volume":"281","author":"Choi","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1002\/hep.22849","article-title":"Hepatitis C virus core protein triggers hepatic angiogenesis by a mechanism including multiple pathways","volume":"49","author":"Hassan","year":"2009","journal-title":"Hepatology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"30711","DOI":"10.1074\/jbc.M209623200","article-title":"1Hepatitis C virus NS5A protein modulates c-Jun N-terminal kinase through interaction with tumor necrosis factor receptor-associated factor 2","volume":"278","author":"Park","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1053\/j.gastro.2010.03.008","article-title":"Hepatitis C virus regulates transforming growth factor beta1 production through the generation of reactive oxygen species in a nuclear factor kappaB-dependent manner","volume":"138","author":"Lin","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1099\/0022-1317-78-7-1527","article-title":"Hepatitis C virus core protein induces hepatic steatosis in transgenic mice","volume":"78","author":"Moriya","year":"1997","journal-title":"J. Gen. Virol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1038\/2053","article-title":"The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice","volume":"4","author":"Moriya","year":"1998","journal-title":"Nat. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1053\/gast.2002.31001","article-title":"Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus","volume":"122","author":"Lerat","year":"2002","journal-title":"Gastroenterology"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.semcancer.2010.10.007","article-title":"The tumor microenvironment in hepatocellular carcinoma: Current status and therapeutic targets","volume":"21","author":"Yang","year":"2011","journal-title":"Semin. Cancer Biol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1038\/aps.2010.142","article-title":"Tumor initiation and progression in hepatocellular carcinoma: Risk factors, classification, and therapeutic targets","volume":"31","author":"Severi","year":"2010","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1016\/S0002-9440(10)62324-3","article-title":"Transforming growth factor-beta and platelet-derived growth factor signal via c-Jun N-terminal kinase-dependent Smad2\/3 phosphorylation in rat hepatic stellate cells after acute liver injury","volume":"166","author":"Yoshida","year":"2005","journal-title":"Am. J. Pathol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1053\/j.gastro.2009.09.015","article-title":"Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition","volume":"138","author":"Kluwe","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Dzieran, J., Fabian, J., Feng, T., Coulouarn, C., Ilkavets, I., Kyselova, A., Breuhahn, K., Dooley, S., and Meindl-Beinker, N.M. (2013). Comparative analysis of TGF-beta\/Smad signaling dependent cytostasis in human hepatocellular carcinoma cell lines. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0072252"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2405","DOI":"10.1056\/NEJMoa1012912","article-title":"Telaprevir for previously untreated chronic hepatitis C virus infection","volume":"364","author":"Jacobson","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.1002\/hep.27113","article-title":"Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection","volume":"59","author":"Kumada","year":"2014","journal-title":"Hepatology"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/S0140-6736(13)62121-2","article-title":"Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): An open-label, randomised, phase 2 trial","volume":"383","author":"Lawitz","year":"2014","journal-title":"Lancet"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1007\/s12325-015-0258-5","article-title":"Early View of the Effectiveness of New Direct-Acting Antiviral (DAA) Regimens in Patients with Hepatitis C Virus (HCV)","volume":"32","author":"Walker","year":"2015","journal-title":"Adv. Ther."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Puoti, M., Foster, G.R., Wang, S., Mutimer, D., Gane, E., Moreno, C., Chang, T.T., Lee, S.S., Marinho, R., and DuFour, J.F. (2018). High SVR12 with 8-week and 12-week Glecaprevir\/Pibrentasvir: Integrated Analysis of HCV Genotype 1-6 Patients Without Cirrhosis. J. Hepatol.","DOI":"10.1016\/j.jhep.2018.03.007"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1056\/NEJM199910213411702","article-title":"Lamivudine as initial treatment for chronic hepatitis B in the United States","volume":"341","author":"Dienstag","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1056\/NEJMoa020681","article-title":"Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B","volume":"348","author":"Marcellin","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1056\/NEJMoa051285","article-title":"A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B","volume":"354","author":"Chang","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2576","DOI":"10.1056\/NEJMoa066422","article-title":"Telbivudine versus lamivudine in patients with chronic hepatitis B","volume":"357","author":"Lai","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_100","first-page":"33","article-title":"Advances in Nucleotide Antiviral Development from Scientific Discovery to Clinical Applications: Tenofovir Disoproxil Fumarate for Hepatitis B","volume":"1","author":"Lou","year":"2013","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"517","DOI":"10.7326\/0003-4819-132-7-200004040-00002","article-title":"Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy","volume":"132","author":"Shiratori","year":"2000","journal-title":"Ann. Intern. Med."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/S0168-8278(99)80123-8","article-title":"Histological changes in liver biopsies after one year of lamivudine treatment in patients with chronic hepatitis B infection","volume":"30","author":"Suzuki","year":"1999","journal-title":"J. Hepatol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1111\/cei.12259","article-title":"Reversible phospho-Smad3 signaling between tumor-suppression and fibro-carcinogenesis in chronic hepatitis B infection","volume":"176","author":"Deng","year":"2014","journal-title":"Clin. Exp. Immunol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1111\/hepr.12082","article-title":"Phosphorylated Smad2 and Smad3 signaling: Shifting between tumor suppression and fibro-carcinogenesis in chronic hepatitis C","volume":"43","author":"Yamaguchi","year":"2013","journal-title":"Hepatol. Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1002\/hep.23744","article-title":"Outcome of sustained virological responders with histologically advanced chronic hepatitis C","volume":"52","author":"Morgan","year":"2010","journal-title":"Hepatology"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1053\/j.gastro.2009.06.045","article-title":"c-Jun N-terminal kinase-1 from hematopoietic cells mediates progression from hepatic steatosis to steatohepatitis and fibrosis in mice","volume":"137","author":"Kodama","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.gde.2003.12.008","article-title":"Reversibility of oncogene-induced cancer","volume":"14","author":"Felsher","year":"2004","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1944","DOI":"10.1002\/hep.22860","article-title":"Inhibition of c-Jun NH2-terminal kinase switches Smad3 signaling from oncogenesis to tumor- suppression in rat hepatocellular carcinoma","volume":"49","author":"Nagata","year":"2009","journal-title":"Hepatology"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1776","DOI":"10.1172\/JCI200320530","article-title":"Epithelial-mesenchymal transition and its implications for fibrosis","volume":"112","author":"Kalluri","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1083\/jcb.95.1.333","article-title":"Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells","volume":"95","author":"Greenburg","year":"1982","journal-title":"J. Cell Biol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1172\/JCI39104","article-title":"The basics of epithelial-mesenchymal transition","volume":"119","author":"Kalluri","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"5764","DOI":"10.1038\/sj.onc.1208927","article-title":"TGF-beta and epithelial-to-mesenchymal transitions","volume":"24","author":"Zavadil","year":"2005","journal-title":"Oncogene"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1002\/jcp.20730","article-title":"Snail controls differentiation of hepatocytes by repressing HNF4alpha expression","volume":"209","author":"Cicchini","year":"2006","journal-title":"J. Cell. Physiol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"22089","DOI":"10.1074\/jbc.M700998200","article-title":"Transforming growth factor-beta1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro","volume":"282","author":"Kaimori","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"3467","DOI":"10.1242\/jcs.068692","article-title":"Snail1 suppresses TGF-beta-induced apoptosis and is sufficient to trigger EMT in hepatocytes","volume":"123","author":"Franco","year":"2010","journal-title":"J. Cell Sci."},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Liu, J., Eischeid, A.N., and Chen, X.M. (2012). Col1A1 production and apoptotic resistance in TGF-beta1-induced epithelial-to-mesenchymal transition-like phenotype of 603B cells. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0051371"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/S0168-8278(00)80413-4","article-title":"New aspects of hepatic fibrosis","volume":"32","author":"Brenner","year":"2000","journal-title":"J. Hepatol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0014-5793(97)00024-0","article-title":"Transforming growth factor-beta1 induces activation of Ras, Raf-1, MEK and MAPK in rat hepatic stellate cells","volume":"403","author":"Reimann","year":"1997","journal-title":"FEBS Lett."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1786","DOI":"10.1172\/JCI114363","article-title":"Effects of platelet-derived growth factor and other polypeptide mitogens on DNA synthesis and growth of cultured rat liver fat-storing cells","volume":"84","author":"Pinzani","year":"1989","journal-title":"J. Clin. Investig."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1002\/hep.510270222","article-title":"Cellular localization of endothelin-1 and increased production in liver injury in the rat: Potential for autocrine and paracrine effects on stellate cells","volume":"27","author":"Rockey","year":"1998","journal-title":"Hepatology"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1002\/hep.510300406","article-title":"Extracellular signal-regulated kinase activation differentially regulates platelet-derived growth factor\u2019s actions in hepatic stellate cells, and is induced by in vivo liver injury in the rat","volume":"30","author":"Marra","year":"1999","journal-title":"Hepatology"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1053\/jhep.2002.30083","article-title":"Differential regulation of TGF-beta signal in hepatic stellate cells between acute and chronic rat liver injury","volume":"35","author":"Tahashi","year":"2002","journal-title":"Hepatology"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1111\/j.1600-0676.1991.tb00499.x","article-title":"Appearance of alpha-smooth-muscle-actin-positive cells in hepatic fibrosis","volume":"11","author":"Nouchi","year":"1991","journal-title":"Liver"},{"key":"ref_124","first-page":"1233","article-title":"Modulation of alpha smooth muscle actin and desmin expression in perisinusoidal cells of normal and diseased human livers","volume":"138","author":"Kruger","year":"1991","journal-title":"Am. J. Pathol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1080\/00313020701329914","article-title":"The role of epithelial-mesenchymal transition in cancer pathology","volume":"39","author":"Guarino","year":"2007","journal-title":"Pathology"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1038\/ncb1173","article-title":"Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition","volume":"6","author":"Zhou","year":"2004","journal-title":"Nat. Cell Biol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"7443","DOI":"10.1038\/sj.onc.1209091","article-title":"Epithelial-mesenchymal transition in development and cancer: Role of phosphatidylinositol 3\u2032 kinase\/AKT pathways","volume":"24","author":"Larue","year":"2005","journal-title":"Oncogene"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"2255","DOI":"10.1002\/hep.26007","article-title":"Hepatic transforming growth factor beta gives rise to tumor-initiating cells and promotes liver cancer development","volume":"56","author":"Wu","year":"2012","journal-title":"Hepatology"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.canlet.2014.05.008","article-title":"Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma","volume":"352","author":"Fan","year":"2014","journal-title":"Cancer Lett."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"E161","DOI":"10.1002\/ijc.29097","article-title":"A mesenchymal-like phenotype and expression of CD44 predict lack of apoptotic response to sorafenib in liver tumor cells","volume":"136","author":"Fernando","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1038\/ncb1905","article-title":"A SNAIL1-SMAD3\/4 transcriptional repressor complex promotes TGF-beta mediated epithelial-mesenchymal transition","volume":"11","author":"Vincent","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1172\/JCI71104","article-title":"Sustained activation of SMAD3\/SMAD4 by FOXM1 promotes TGF-beta-dependent cancer metastasis","volume":"124","author":"Xue","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/1476-4598-2-20","article-title":"Interfering with TGFbeta-induced Smad3 nuclear accumulation differentially affects TGFbeta-dependent gene expression","volume":"2","author":"Lindemann","year":"2003","journal-title":"Mol. Cancer"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"8230","DOI":"10.1038\/ncomms9230","article-title":"Epigenetic regulation of Smad2 and Smad3 by profilin-2 promotes lung cancer growth and metastasis","volume":"6","author":"Tang","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_135","doi-asserted-by":"crossref","unstructured":"Yang, Y., Liu, Q., Li, Z., Zhang, R., Jia, C., Yang, Z., Zhao, H., Ya, S., Mao, R., and Ailijiang, T. (2018). GP73 promotes epithelial-mesenchymal transition and invasion partly by activating TGF-beta1\/Smad2 signaling in hepatocellular carcinoma. Carcinogenesis.","DOI":"10.1093\/carcin\/bgy010"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.lfs.2018.03.004","article-title":"G protein coupled receptors can transduce signals through carboxy terminal and linker region phosphorylation of Smad transcription factors","volume":"199","author":"Dayti","year":"2018","journal-title":"Life Sci."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.18632\/oncotarget.13852","article-title":"NEDD9 may regulate hepatocellular carcinoma cell metastasis by promoting epithelial-mesenchymal-transition and stemness via repressing Smad7","volume":"8","author":"Wang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_138","doi-asserted-by":"crossref","unstructured":"Zhou, H.H., Chen, L., Liang, H.F., Li, G.Z., Zhang, B.X., and Chen, X.P. (2016). Smad3 Sensitizes Hepatocelluar Carcinoma Cells to Cisplatin by Repressing Phosphorylation of AKT. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17040610"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1002\/hep.27887","article-title":"MicroRNA-125b attenuates epithelial-mesenchymal transitions and targets stem-like liver cancer cells through small mothers against decapentaplegic 2 and 4","volume":"62","author":"Zhou","year":"2015","journal-title":"Hepatology"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"2552","DOI":"10.3892\/ol.2017.6429","article-title":"miRNA-708 functions as a tumour suppressor in hepatocellular carcinoma by targeting SMAD3","volume":"14","author":"Li","year":"2017","journal-title":"Oncology Lett."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.febslet.2014.11.031","article-title":"MicroRNA-520g induces epithelial-mesenchymal transition and promotes metastasis of hepatocellular carcinoma by targeting SMAD7","volume":"589","author":"Kan","year":"2015","journal-title":"FEBS Lett."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.cellsig.2018.03.009","article-title":"Thrombin promotes PAI-1 expression and migration in keratinocytes via ERK dependent Smad linker region phosphorylation","volume":"47","author":"Talati","year":"2018","journal-title":"Cell Signal."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1124\/jpet.117.244483","article-title":"Flavopiridol inhibits TGF-\u03b2-stimulated biglycan synthesis by blocking linker region phosphorylation and nuclear translocation of Smad2","volume":"365","author":"Rostam","year":"2018","journal-title":"J. Pharmacol. Exp. Ther."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/10\/6\/183\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:07:24Z","timestamp":1760195244000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/10\/6\/183"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,6,5]]},"references-count":143,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2018,6]]}},"alternative-id":["cancers10060183"],"URL":"https:\/\/doi.org\/10.3390\/cancers10060183","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,6,5]]}}}