Journal Article

Alterations in genomic profiles during tumor progression in a mouse model of follicular thyroid carcinoma

Hao Ying, Hideyo Suzuki, Hiroko Furumoto, Robert Walker, Paul Meltzer, Mark C. Willingham and Sheue-Yann Cheng

in Carcinogenesis

Volume 24, issue 9, pages 1467-1479
Published in print September 2003 | ISSN: 0143-3334
Published online September 2003 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgg111
Alterations in genomic profiles during tumor progression in a mouse model of follicular thyroid carcinoma

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The molecular genetics underlying thyroid carcinogenesis is not well understood. We have recently created a mutant mouse by targeting a mutation (PV) into the thyroid hormone receptor β gene (TRβPV mouse). TRβPV/PV mice spontaneously develop follicular thyroid carcinoma through pathological progression of hyperplasia, capsular and vascular invasion, anaplasia and eventually metastasis to distant organs. TRβPV/PV mice provide an unusual opportunity to study the alterations in gene regulation that occur during thyroid carcinogenesis. To this end, we profiled the genomic changes in the thyroids of TRβPV/PV mice at 6 months of age, at which time metastasis had begun. From arrays of 20 000 mouse cDNAs, 185 genes were up-regulated (2–17-fold) and 92 were down-regulated (2–20-fold). Functional clustering of named genes with reported functions (100 genes) indicated that ∼39% of these genes were tumor-, metastasis/invasion- and cell-cycle-related. Among the activated tumor-related genes identified, cyclin D1, pituitary tumor transforming gene-1, cathespin D and transforming growth factor α were also found to over-express in human thyroid cancers. Analyses of the gene profiles suggested that the signaling pathways mediated by thyrotropin, peptide growth factors, transforming growth factor-β, tumor necrosis factor-α and nuclear factor-κB were activated, whereas pathways mediated by peroxisome proliferation activated receptor γ were repressed. These results indicate that complex alterations of multiple signaling pathways contribute to thyroid carcinogenesis. The critical genes associated with thyroid follicular carcinogenesis uncovered in the present study could serve as signature genes for diagnostic purposes, as well as for possible therapeutic targets.

Keywords: DAD-1, defender against cell death-1; EGF, epidermal growth factor; FTC, follicular thyroid carcinoma; Gsα, guanine nucleotide stimulatory factor a subunit; IGF, insulin-like growth factor; IκB, inhibitor of κB; LpL, lipoprotein lipase; LPS, lipopolysaccharide; MGI IDs, Mouse Genome Informatics Accession Identification Numbers; NF-κB, nuclear factor κB; PAX8, paired box gene 8; PPARγ1, peroxisome proliferator activated receptor γ1; PTTG-1, pituitary tumor transforming gene-1; RTH, thyroid hormone resistance syndrome; TGFβ, transforming growth factor β; TNF-α, tumor necrosis factor-α; TR, thyroid hormone receptor; TSH, thyrotropin

Journal Article.  8396 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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