Alterations in genomic profiles during tumor progression in a mouse model of follicular thyroid carcinoma.
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 beta gene (TRbetaPV mouse). TRbetaPV/PV mice spontaneously develop follicular thyroid carcinoma through pathological progression of hyperplasia, capsular and vascular invasion, anaplasia and eventually metastasis to distant organs. TRbetaPV/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 TRbetaPV/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 approximately 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 alpha 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-beta, tumor necrosis factor-alpha and nuclear factor-kappaB were activated, whereas pathways mediated by peroxisome proliferation activated receptor gamma 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.
Ying
Hao
H
Laboratory of Molecular Biology, National Cancer Institute, Winston-Salem, NC 27157-1072, USA.
Suzuki
Hideyo
H
Furumoto
Hiroko
H
Walker
Robert
R
Meltzer
Paul
P
Willingham
Mark C
MC
Cheng
Sheue-Yann
SY
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D018265:Carcinoma, Papillary, Follicular; D002453:Cell Cycle / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D011988:Receptors, Thyroid Hormone / Q000235:genetics; D015398:Signal Transduction; D037042:Thyroid Hormone Receptors beta; D013964:Thyroid Neoplasms / Q000235:genetics*
D011988:Receptors, Thyroid Hormone; D037042:Thyroid Hormone Receptors beta