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.
|Nabhan, Fadi; Ringel, Matthew D (2016) Thyroid nodules and cancer management guidelines: comparisons and controversies. Endocr Relat Cancer :|
|Shirley, Lawrence A; McCarty, Samantha; Yang, Ming-Chen et al. (2016) Integrin-linked kinase affects signaling pathways and migration in thyroid cancer cells and is a potential therapeutic target. Surgery 159:163-70|
|Tomsic, Jerneja; Fultz, Rebecca; Liyanarachchi, Sandya et al. (2016) HABP2 G534E Variant in Papillary Thyroid Carcinoma. PLoS One 11:e0146315|
|Harshman, Sean W; Canella, Alessandro; Ciarlariello, Paul D et al. (2016) Proteomic characterization of circulating extracellular vesicles identifies novel serum myeloma associated markers. J Proteomics 136:89-98|
|Kirschner, Lawrence S; Qamri, Zahida; Kari, Suresh et al. (2016) Mouse models of thyroid cancer: A 2015 update. Mol Cell Endocrinol 421:18-27|
|Justiniano, Steven E; McElroy, Joseph P; Yu, Lianbo et al. (2016) Genetic variants in thyroid cancer distant metastases. Endocr Relat Cancer 23:L33-6|
|Wang, Yanqiang; Li, Wei; Phay, John E et al. (2016) Primary Cell Culture Systems for Human Thyroid Studies. Thyroid 26:1131-40|
|Nagy, Rebecca; Ringel, Matthew D (2015) Genetic predisposition for nonmedullary thyroid cancer. Horm Cancer 6:13-20|
|Yehia, Lamis; Niazi, Farshad; Ni, Ying et al. (2015) Germline Heterozygous Variants in SEC23B Are Associated with Cowden Syndrome and Enriched in Apparently Sporadic Thyroid Cancer. Am J Hum Genet 97:661-76|
|Tomsic, Jerneja; He, Huiling; de la Chapelle, Albert (2015) HABP2 Mutation and Nonmedullary Thyroid Cancer. N Engl J Med 373:2086|
Showing the most recent 10 out of 101 publications