title: The effect of oncoprotein v-erbA on thyroid hormone-regulated genes in hepatocytes and their potential role in hepatocellular carcinoma.
abstract: Mutant forms of thyroid hormone receptor (TR) with dominant negative activity are frequently found in human hepatocellular carcinoma (HCC). Interestingly, the v-erbA oncogene, known to exert a dominant-negative effect on the expression of thyroid hormone (T3)-responsive genes, led to the development of HCC in a transgenic mouse model. Thus it is possible that the oncogenic activity of v-erbA in hepatocytes may be mediated by its dominant negative activity on T3-responsive genes. Microarray analysis was used to identify genes differentially expressed in murine hepatocytes in culture (AML12 cells) stably transfected with v-erbA and exposed to T3. The Affymetrix GeneChip Mouse Genome 430 2.0 array consisted of over 39,000 transcripts representing well-known genes. We have identified twenty T3-responsive genes that are negatively regulated by v-erbA at 3 h, and eighteen genes at 24 h, such as follistatin, activin βC, thrombomodulin, Six1, Rasgrp3 and Ndrg2, as well as genes that are regulated by v-erbA only, such as angiopoietin 1 and Igfr2. We have identified T3 responsive genes that are dysregulated by v-erbA. These genes are known to be involved in carcinogenesis. Our studies may provide insight into the potential role of mutant forms of TR in the pathogenesis of HCC.
authors.affiliation: Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Tereza
authors.initials: T
authors.lastname: Ventura-Holman
authors.forename: Abulkhair
authors.initials: A
authors.lastname: Mamoon
authors.forename: Maria C
authors.initials: MC
authors.lastname: Subauste
authors.forename: Jose S
authors.initials: JS
authors.lastname: Subauste
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002460:Cell Line; D015972:Gene Expression Regulation, Neoplastic; D005799:Genes, Dominant; D018776:Genes, erbA; D008113:Liver Neoplasms / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins; D018774:Oncogene Proteins v-erbA / Q000235:genetics* / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism*; D013997:Time Factors
chemical_list: D015513:Oncogene Proteins; D018774:Oncogene Proteins v-erbA; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones