title: Redifferentiation and induction of tumor suppressors miR-122 and miR-375 by the PAX8/PPARγ fusion protein inhibits anaplastic thyroid cancer: a novel therapeutic strategy.
abstract: Anaplastic thyroid cancer (ATC) is an aggressive, fatal disease unresponsive to traditional therapies, generating a need to develop effective therapies. The PAX8/PPARγ fusion protein (PPFP) has been shown to favorably modulate tumor growth in follicular thyroid cancer, prompting our evaluation of its efficacy to inhibit ATC cell and tumor growth in vitro and in vivo. PPFP was constitutively expressed in five ATC cell lines: BHT-101, FRO, C-643, KTC-2 and KTC-3, and inhibited cell growth in four of five cell lines and xenograft tumor growth in four of four cell lines. PPFP-mediated growth inhibition involved multiple mechanisms, including upregulation of miR-122 and miR-375, associated with decreased angiogenesis and AKT pathway inactivation, respectively. Also, PPFP expression resulted in marked increase of thyroid-specific marker transcripts, including PAX8, thyroid peroxidase (TPO), sodium iodide symporter (NIS) and thyroglobulin, to varying degrees by activating their respective promoters, suggesting that PPFP induced cellular redifferentiation. Functional studies demonstrate that increased NIS messenger RNA is not associated with increased 125I uptake. However, ectopic expression of wild-type NIS-induced perchlorate-sensitive iodine uptake, suggesting that endogenous NIS in ATC cell lines is defective. As current treatment for ATC is only palliative, overexpression of PPFP may offer a novel therapeutic strategy for the treatment of ATC.
authors.affiliation: Department of Medicine, Division of Endocrinology, Mayo Clinic & Foundation, Rochester, MN 55905, USA. honey@mayo.edu
authors.forename: H V
authors.initials: HV
authors.lastname: Reddi
authors.forename: C B
authors.initials: CB
authors.lastname: Driscoll
authors.forename: P
authors.initials: P
authors.lastname: Madde
authors.forename: D
authors.initials: D
authors.lastname: Milosevic
authors.forename: R M
authors.initials: RM
authors.lastname: Hurley
authors.forename: S J
authors.initials: SJ
authors.lastname: McDonough
authors.forename: J
authors.initials: J
authors.lastname: Hallanger-Johnson
authors.forename: B
authors.initials: B
authors.lastname: McIver
authors.forename: N L
authors.initials: NL
authors.lastname: Eberhardt
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion; D065646:Thyroid Carcinoma, Anaplastic; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D014162:Transfection; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: C531907:MIRN122 microRNA, human; C540933:MIRN375 microRNA, human; D035683:MicroRNAs; D015514:Oncogene Proteins, Fusion; C551995:PAX8-PPARgamma fusion protein, human