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.
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