The RET/PTC oncogene, a rearranged form of the RET receptor tyrosine kinase, is believed to play an important role in the pathogenesis of papillary thyroid cancer (PTC), in particular in pediatric patients and those with prior radiation exposure. The long-term goal of the proposed project is to understand the underlying mechanisms of the effects of RET/PTC oncogene on tumorigenesis, progression, and radioiodine therapy of human PTC. In this proposal, three specific aims are identified.
In Aim 1, we will investigate the onset of RET/PTC1 in thyroid tumorigenesis and the requirement of RET/PTC1 in tumor maintenance/ progression. We are generating doxycycline-inducible thyroid-targeted RET/PTC1-luciferase bi-transgenic mice;such that RET/PTC1 expression can be modulated by administration of doxycycline and thyroid tumor formation can be non-invasively monitored by MS? imaging. We hypothesize that RET/PTC mediated tumor formation is modulated by the intrinsic proliferation capacity of thyrocytes at the time of RET/PTC activation.
In Aim 2, we will delineate the underlying mechanisms of NIS modulation by phosphorylation and protein complex formation. We have identified four in vivo phosphorylation sites in NIS and have demonstrated possible significance of these four phosphorylation sites in modulating NIS activity. We will further characterize the functional significance of these four phosphorylation sites and identify signaling/kinases that modulate these phosphorylation sites. In addition, we will examine whether differences in NIS phosphorylation and NIS protein complexes contributes to the discordance between NIS cell surface levels and NIS activity.
In Aim 3, we will screen for agents that selectively increase radioiodine accumulation in thyroid tumors using a pre-clinical animal model and examine RET/PTC1 effects on radionuclide uptake and retention in the thyroid of live animals.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ohio State University
United States
Zip Code
Yu, Wanfeng; Ni, Ying; Saji, Motoyasu et al. (2017) Cowden syndrome-associated germline succinate dehydrogenase complex subunit D (SDHD) variants cause PTEN-mediated down-regulation of autophagy in thyroid cancer cells. Hum Mol Genet 26:1365-1375
Gudmundsson, Julius; Thorleifsson, Gudmar; Sigurdsson, Jon K et al. (2017) A genome-wide association study yields five novel thyroid cancer risk loci. Nat Commun 8:14517
Azmat, Umal; Porter, Kyle; Senter, Leigha et al. (2017) Thyroglobulin Liquid Chromatography-Tandem Mass Spectrometry Has a Low Sensitivity for Detecting Structural Disease in Patients with Antithyroglobulin Antibodies. Thyroid 27:74-80
Chen, Hannah H; Händel, Norman; Ngeow, Joanne et al. (2017) Immune dysregulation in patients with PTEN hamartoma tumor syndrome: Analysis of FOXP3 regulatory T cells. J Allergy Clin Immunol 139:607-620.e15
Rossfeld, Kara K; Justiniano, Steven E; Ding, Haiming et al. (2017) Biological Evaluation of a Fluorescent-Imaging Agent for Medullary Thyroid Cancer in an Orthotopic Model. J Clin Endocrinol Metab 102:3268-3277
Saporito, Donika; Brock, Pamela; Hampel, Heather et al. (2017) Penetrance of a rare familial mutation predisposing to papillary thyroid cancer. Fam Cancer :
Byrd, Victoria; Getz, Ted M; Padmanabhan, Roshan et al. (2017) Microbiome in PTEN hamartoma tumor syndrome. Endocr Relat Cancer :
Tomsic, Jerneja; Fultz, Rebecca; Liyanarachchi, Sandya et al. (2017) Variants in microRNA genes in familial papillary thyroid carcinoma. Oncotarget 8:6475-6482
Ni, Ying; Seballos, Spencer; Fletcher, Benjamin et al. (2017) Germline compound heterozygous poly-glutamine deletion in USF3 may be involved in predisposition to heritable and sporadic epithelial thyroid carcinoma. Hum Mol Genet 26:243-257
Ashtekar, Amruta; Huk, Danielle; Magner, Alexa et al. (2017) Sdhd ablation promotes thyroid tumorigenesis by inducing a stem-like phenotype. Endocr Relat Cancer 24:579-591

Showing the most recent 10 out of 122 publications