title: Adipogenic Differentiation of Thyroid Cancer Cells Through the Pax8-PPARγ Fusion Protein Is Regulated by Thyroid Transcription Factor 1 (TTF-1).
abstract: A subset of thyroid carcinomas contains a t(2;3)(q13;p25) chromosomal translocation that fuses paired box gene 8 (PAX8) with the peroxisome proliferator-activated receptor γ gene (PPARG), resulting in expression of a PAX8-PPARγ fusion protein, PPFP. We previously generated a transgenic mouse model of PPFP thyroid carcinoma and showed that feeding the PPARγ agonist pioglitazone greatly decreased the size of the primary tumor and prevented metastatic disease in vivo The antitumor effect correlates with the fact that pioglitazone turns PPFP into a strongly PPARγ-like molecule, resulting in trans-differentiation of the thyroid cancer cells into adipocyte-like cells that lose malignant character as they become more differentiated. To further study this process, we performed cell culture experiments with thyrocytes from the PPFP mouse thyroid cancers. Our data show that pioglitazone induced cellular lipid accumulation and the expression of adipocyte marker genes in the cultured cells, and shRNA knockdown of PPFP eliminated this pioglitazone effect. In addition, we found that PPFP and thyroid transcription factor 1 (TTF-1) physically interact, and that these transcription factors bind near each other on numerous target genes. TTF-1 knockdown and overexpression studies showed that TTF-1 inhibits PPFP target gene expression and impairs adipogenic trans-differentiation. Surprisingly, pioglitazone repressed TTF-1 expression in PPFP-expressing thyrocytes. Our data indicate that TTF-1 interacts with PPFP to inhibit the pro-adipogenic response to pioglitazone, and that the ability of pioglitazone to decrease TTF-1 expression contributes to its pro-adipogenic action.
authors.affiliation: From the Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical Center, Ann Arbor, Michigan 48109-5678 and bxu@umich.edu.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.affiliation: From the Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical Center, Ann Arbor, Michigan 48109-5678 and.
authors.forename: Michael
authors.initials: M
authors.lastname: O'Donnell
authors.affiliation: From the Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical Center, Ann Arbor, Michigan 48109-5678 and.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: O'Donnell
authors.affiliation: From the Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical Center, Ann Arbor, Michigan 48109-5678 and.
authors.forename: Jingcheng
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109-2218.
authors.forename: Yanxiao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109-2218.
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Sartor
authors.affiliation: From the Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical Center, Ann Arbor, Michigan 48109-5678 and.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Koenig
mesh_terms: D050156:Adipogenesis; D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D051379:Mice; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D000072636:PAX8 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors
chemical_list: C000614414:Nkx2-1 protein, mouse; C000614416:Nkx2-1 protein, rat; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D000072636:PAX8 Transcription Factor; D047495:PPAR gamma; C499496:Pax8 protein, mouse; C499497:Pax8 protein, rat; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors
keywords: cancer; differentiation; fusion protein; gene expression; thyroid