IGF2 is up-regulated by epigenetic mechanisms in Hepatocellular Carcinoma and is an actionable oncogene product in experimental models

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RECERCAT Home > Universitat de Barcelona > IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer > Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) > View document

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dc.contributor.author	Martínez Quetglas, Iris
dc.contributor.author	Pinyol, Roser
dc.contributor.author	Dauch, Daniel
dc.contributor.author	Torrecilla, Sara
dc.contributor.author	Tovar, Victoria
dc.contributor.author	Moeini, Agrin
dc.contributor.author	Alsinet, Clara
dc.contributor.author	Portela, Anna
dc.contributor.author	Rodríguez-Carunchio, Leonardo
dc.contributor.author	Sole, Manel
dc.contributor.author	Lujambio, Amaia
dc.contributor.author	Villanueva, Augusto
dc.contributor.author	Thung, Swan N.
dc.contributor.author	Esteller, Manel
dc.contributor.author	Zender, Lars
dc.contributor.author	Llovet i Bayer, Josep Maria
dc.date	2018-03-01T18:19:53Z
dc.date	2018-03-01T18:19:53Z
dc.date	2016-12-01
dc.date	2018-03-01T18:19:53Z
dc.identifier	0016-5085
dc.identifier	677366
dc.identifier	27614046
dc.identifier.uri	http://hdl.handle.net/2445/120388
dc.description	BACKGROUND & AIMS: Effective treatments are urgently needed for hepatocellular carcinoma (HCC), which is usually diagnosed at advanced stages. Signaling via the insulin-like growth factor (IGF) pathway is aberrantly activated in HCC by IGF2 overexpression. We aimed to elucidate the mechanism of IGF2 overexpression and its oncogenic activities and evaluate the anti-tumor effects of reducing IGF2 signaling. METHODS: We obtained 228 HCC samples from patients who underwent liver resection, 168 paired non-tumor adjacent cirrhotic liver samples, and 10 non-tumor liver tissues from patients undergoing resection for hepatic hemangioma. We analyzed gene expression, microRNA, and DNA methylation profiles for all samples, focusing on genes in the IGF signaling pathway. IGF2 was expressed in SNU449 and PLC5 HCC cells and knocked down with small hairpin RNAs in Hep3B and Huh7 cell lines. We analyzed these cells for proliferation, apoptosis, migration, and colony formation. We performed studies in mice engineered to express Myc and Akt1 in liver, which develop liver tumors, with or without hepatic expression of Igf2. Mice with xenograft tumors grown from HCC cells were given a monoclonal antibody against IGF1 and IGF2 (xentuzumab), along with sorafenib; tumor growth was measured and tissues were analyzed by immunohistochemistry and immunoblots. RESULTS: Levels of IGF2 messenger RNA and protein were increased > 20-fold in 15% of human HCC tissues compared with non-tumor liver tissues. Methylation at the fetal promoters of IGF2 was reduced in the HCC samples and cell lines that overexpressed IGF2, compared with those that did not overexpress this gene, and non-tumor tissues. Tumors that overexpressed IGF2 had gene expression patterns significantly associated with hepatic progenitor cell features, stellate cell activation, NOTCH signaling, and an aggressive phenotype (P < .0001). In mice engineered to express Myc and Akt1 in liver, co-expression of Igf2 accelerated formation of liver tumors, compared to mice with livers expressing only Myc and Akt1, and shortened survival times (P = .02). The antibody xentuzumab blocked phosphorylation of IGF1 receptor in HCC cell lines and reduced their proliferation and colony formation. In mice with xenograft tumors, injection of xentuzumab, with or without sorafenib, slowed tumor growth and increased survival times compared to vehicle or sorafenib alone. Xentuzumab inhibited phosphorylation of IGF1 receptor and AKT and reduced decreased tumor vascularization compared with vehicle. CONCLUSIONS: A large proportion of HCC samples were found to overexpress IGF2, via demethylation of its fetal promoter. Overexpression of IGF2 accelerates formation of liver tumors in mice with hepatic expression of MYC and AKT1, via activation of IGF1 receptor signaling. An antibody against IGF1 and IGF2 slows growth of xenograft tumors and increases survival of these mice.
dc.format	79 p.
dc.format	application/pdf
dc.language	eng
dc.publisher	Elsevier
dc.relation	Versió postprint del document publicat a: https://doi.org/10.1053/j.gastro.2016.09.001
dc.relation	Gastroenterology, 2016, vol. 151, num. 6, p. 1192-1205
dc.relation	https://doi.org/10.1053/j.gastro.2016.09.001
dc.relation	info:eu-repo/grantAgreement/EC/H2020/667273/EU//HEP-CAR
dc.relation	info:eu-repo/grantAgreement/EC/FP7/259744/EU//HEPTROMIC
dc.rights	cc-by-nc-nd (c) AGA Institute, 2016
dc.rights	http://creativecommons.org/licenses/by-nc-nd/3.0/es
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	Càncer de fetge
dc.subject	Models animals en la investigació
dc.subject	Oncogens
dc.subject	Carcinogènesi
dc.subject	Epigenètica
dc.subject	Liver cancer
dc.subject	Animal models in research
dc.subject	Oncogenes
dc.subject	Carcinogenesis
dc.subject	Epigenetics
dc.title	IGF2 is up-regulated by epigenetic mechanisms in Hepatocellular Carcinoma and is an actionable oncogene product in experimental models
dc.type	info:eu-repo/semantics/article
dc.type	info:eu-repo/semantics/acceptedVersion

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