Publications by authors named "Sissy M Jhiang"

47 Publications

Personalized radioiodine therapy for thyroid cancer patients with known disease.

Fac Rev 2021 7;10:36. Epub 2021 Apr 7.

Department of Mechanical and Aerospace Engineering, The Ohio State University, Columbus, OH 43210, USA.

Radioactive iodine (RAI) I is a targeted therapy for patients with RAI-avid follicular cell-derived thyroid cancer. However, the responsiveness to I therapy varies among thyroid cancer patients mainly owing to differential RAI uptake and RAI radiosensitivity among patients' lesions. A personalized approach to maximize I therapeutic efficacy is proposed based on recent scientific advances and future opportunities.
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http://dx.doi.org/10.12703/r/10-36DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103907PMC
April 2021

NIS in non-thyroidal tissues and impact on thyroid cancer therapy.

Endocr Relat Cancer 2021 May 1. Epub 2021 May 1.

J Sipos, Endocrinology, The Ohio State University, Columbus, 43210, United States.

Radioiodine (131I) has been used to ablate thyroid tissue not removed by surgery or to treat differentiated thyroid cancer that has metastasized to other parts of the body for the past 80 years. However, the Na+/I- symporter (NIS), which mediates active iodide uptake into thyroid follicular cells, is also expressed in several non-thyroidal tissues. This NIS expression permits 131I accumulation and radiation damage in these non-target tissues, which accounts for the adverse effects of radioiodine therapy. We will review the data regarding the expression, function, and regulation of NIS in non-thyroidal tissues. We will explain the seemingly paradoxical adverse effects induced by 131I: the self-limited gastrointestinal adverse effects in contrast to the permanent salivary dysfunction that is seen after 131I therapy. We propose that prospective studies are needed to uncover the time-course of pathological processes underlying development and progression or ultimate resolution of 131I-induced salivary ductal obstruction and nasolacrimal duct obstruction. Finally, preventive measures and early therapeutic interventions that can be applied potentially to eliminate or alleviate long-term radioiodine adverse effects will be discussed.
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http://dx.doi.org/10.1530/ERC-21-0035DOI Listing
May 2021

Prospects for Redifferentiating Agents in the Use of Radioactive Iodine Therapy for Thyroid Cancer.

Thyroid 2020 04 26;30(4):471-473. Epub 2020 Mar 26.

Division of Endocrinology and Metabolism, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.

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http://dx.doi.org/10.1089/thy.2020.0143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187962PMC
April 2020

Risk Haplotypes Uniquely Associated with Radioiodine-Refractory Thyroid Cancer Patients of High African Ancestry.

Thyroid 2019 04 13;29(4):530-539. Epub 2019 Feb 13.

1 Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio.

Background: Thyroid cancer patients with radioiodine-refractory (RAI-R) disease, resulting from insufficient RAI delivery and/or RAI resistance, have increased mortality and limited treatment options. To date, studies have largely focused on tumor mutations associated with different stages of disease, which could provide prognostic value for RAI-R disease. It was hypothesized that germline variants contributing to intrinsic differences in iodine metabolism, tumor microenvironment, and/or immune surveillance are associated with RAI-R disease.

Methods: Whole-genome genotyping data analysis was performed on 1145 Caucasian (CAU) patients, 244 of whom were RAI-R, and 55 African American (AA) patients, nine of whom were RAI-R. Germline-variant association studies were conducted using candidate genes involved in iodine metabolism or DNA-damage repair, as well as genome-wide association analysis. Initial data indicated several notable variants in a small number of patients (n = 7), who were later determined to be AA patients of >80% African ancestry (n = 37). This led to the study focusing on germline single nucleotide polymorphisms uniquely associated with RAI-R AA patients. Sanger sequencing was performed to validate risk alleles and identify the incidence of the common somatic mutations BRAF, NRAS, and HRAS in AA patients whose primary tumor samples were available (28/55).

Results: TG, BRCA1, and NSMCE2 haplotypes were identified as being uniquely associated with RAI-R AA patients of >80% African ancestry. All patients with the TG haplotype (n = 4) had a biochemical incomplete response to RAI therapy. Patients with the NSMCE2 haplotype (n = 4) were diagnosed at a young age (13, 17, 17, and 26 years old) with distant metastatic disease at initial diagnosis. The BRCA1 haplotype co-occurred in three out of four patients with the NSMCE2 haplotype. The incidence of BRAF appears lower in papillary thyroid carcinomas from AA patients of >80% African ancestry (3/14; 21%) than in AA patients of <80% African ancestry (6/9; 67%), albeit only just approaching statistical significance (p = 0.077). The tumors available from three RAI-R AA patients were negative for BRAF, NRAS, and HRAS.

Conclusions: The identification of candidate RAI-R risk haplotypes may allow early stratification of clinical manifestations of RAI-R disease followed by early intervention and personalized treatment strategies. Functional annotation of candidate RAI-R risk haplotypes may provide insights into the mechanisms underlying RAI-R disease.
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http://dx.doi.org/10.1089/thy.2018.0687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457887PMC
April 2019

The rs2910164 Genetic Variant of miR-146a-3p Is Associated with Increased Overall Mortality in Patients with Follicular Variant Papillary Thyroid Carcinoma.

Int J Mol Sci 2018 Feb 26;19(3). Epub 2018 Feb 26.

Genomic Medicine, Medical University of Warsaw, 02-097 Warsaw, Poland.

Aberrant expression of the sodium-iodide symporter (NIS) and the resistance to post-operative radioactive iodide treatment is a crucial cause of higher mortality of some thyroid cancer patients. In this study, we analyzed the impact of miR-146a on the expression and function of NIS and on the overall survival of thyroid cancer patients. The study included 2441 patients (2163 women; 278 men); including 359 cases with follicular variant of papillary thyroid carcinoma (fvPTC). miR: interactions were analyzed in cell lines using in vivo binding and inhibition assays and radioactive iodine uptake assays. Tumor/blood DNA was used for rs2910164 genotyping. Overall survival was assessed retrospectively. In the results, we showed that miR-146a-3p directly binds to and inhibits . Inhibition of miR-146a-3p restores the expression and function of increasing radioactive iodine uptake. Rs2910164 functional variant within miR-146a-3p is associated with increased overall mortality among fvPTC female patients. The deaths per 1000 person-years were 29.7 in CC carriers vs. 5.08 in GG/GC-carriers (HR = 6.21, ). Higher mortality of CC vs. GG/GC carriers was also observed in patients with lower clinical stage (HR = 22.72, < 0.001), smaller tumor size (pT1/pT2) (HR = 25.05, ), lack of extrathyroidal invasion (HR = 9.03, = 0.02), lack of nodular invasion (HR = 7.84, ), lack of metastases (HR = 6.5, = 0.005) and older (age at diagnosis >50 years) (HR = 7.8, ). MiR-146a-3p underwent somatic mutations in 16.1% of analyzed specimens, mainly towards the deleterious C allele. In this report we propose a novel molecular marker of the clinical outcome of fvPTC patients. Rs2910164 increases the overall mortality with inhibition of NIS and disruption of radioiodine uptake as a possible mechanism.
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http://dx.doi.org/10.3390/ijms19030655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877516PMC
February 2018

Modeling and calibrating nonlinearity and crosstalk in back focal plane interferometry for three-dimensional position detection.

Opt Lett 2017 Oct;42(19):3948-3951

Back focal plane (BFP) interferometry is frequently used to detect the motion of a single laser trapped bead in a photonic force microscope (PFM) system. Whereas this method enables high-speed and high-resolution position measurement, its measurement range is limited by nonlinearity coupled with crosstalk in three-dimensional (3-D) measurement, and validation of its measurement accuracy is not trivial. This Letter presents an automated calibration system in conjunction with a 3-D quadratic model to render rapid and accurate calibration of the laser measurement system. An actively controlled three-axis laser steering system and a high-speed vision-based 3-D particle tracking system are integrated to the PFM system to enable rapid calibration. The 3-D quadratic model is utilized to correct for nonlinearity and crosstalk and, thus, extend the 3-D position detection volume of BFP interferometry. We experimentally demonstrated a 12-fold increase in detection volume when applying the method to track the motion of a 2.0 μm laser trapped polystyrene bead.
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http://dx.doi.org/10.1364/OL.42.003948DOI Listing
October 2017

ablation promotes thyroid tumorigenesis by inducing a stem-like phenotype.

Endocr Relat Cancer 2017 11 19;24(11):579-591. Epub 2017 Sep 19.

Department of Cancer Biology and GeneticsThe Ohio State University, Columbus, Ohio, USA

Mutations in genes encoding enzymes in the tricarboxylic acid cycle (TCA, also known as the Krebs cycle) have been implicated as causative genetic lesions in a number of human cancers, including renal cell cancers, glioblastomas and pheochromocytomas. In recent studies, missense mutations in the succinate dehydrogenase (SDH) complex have also been proposed to cause differentiated thyroid cancer. In order to gain mechanistic insight into this process, we generated mice lacking the SDH subunit D (Sdhd) in the thyroid. We report that these mice develop enlarged thyroid glands with follicle hypercellularity and increased proliferation. , human thyroid cell lines with knockdown of exhibit an enhanced migratory capability, despite no change in proliferative capacity. Interestingly, these cells acquire stem-like features which are also observed in the mouse tumors. The stem-like characteristics are reversed by α-ketoglutarate, suggesting that SDH-associated tumorigenesis results from dedifferentiation driven by an imbalance in cellular metabolites of the TCA cycle. The results of this study reveal a metabolic vulnerability for potential future treatment of SDH-associated neoplasia.
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http://dx.doi.org/10.1530/ERC-17-0229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650926PMC
November 2017

Automated MicroSPECT/MicroCT Image Analysis of the Mouse Thyroid Gland.

Thyroid 2017 11 19;27(11):1433-1440. Epub 2017 Oct 19.

2 Department of Physiology and Cell Biology, The Ohio State University , Columbus, Ohio.

Background: The ability of thyroid follicular cells to take up iodine enables the use of radioactive iodine (RAI) for imaging and targeted killing of RAI-avid thyroid cancer following thyroidectomy. To facilitate identifying novel strategies to improve I therapeutic efficacy for patients with RAI refractory disease, it is desired to optimize image acquisition and analysis for preclinical mouse models of thyroid cancer.

Methods: A customized mouse cradle was designed and used for microSPECT/CT image acquisition at 1 hour (t1) and 24 hours (t24) post injection of I, which mainly reflect RAI influx/efflux equilibrium and RAI retention in the thyroid, respectively. FVB/N mice with normal thyroid glands and TgBRAF mice with thyroid tumors were imaged. In-house CTViewer software was developed to streamline image analysis with new capabilities, along with display of 3D voxel-based I gamma photon intensity in MATLAB.

Results: The customized mouse cradle facilitates consistent tissue configuration among image acquisitions such that rigid body registration can be applied to align serial images of the same mouse via the in-house CTViewer software. CTViewer is designed specifically to streamline SPECT/CT image analysis with functions tailored to quantify thyroid radioiodine uptake. Automatic segmentation of thyroid volumes of interest (VOI) from adjacent salivary glands in t1 images is enabled by superimposing the thyroid VOI from the t24 image onto the corresponding aligned t1 image. The extent of heterogeneity in I accumulation within thyroid VOIs can be visualized by 3D display of voxel-based I gamma photon intensity.

Conclusions: MicroSPECT/CT image acquisition and analysis for thyroidal RAI uptake is greatly improved by the cradle and the CTViewer software, respectively. Furthermore, the approach of superimposing thyroid VOIs from t24 images to select thyroid VOIs on corresponding aligned t1 images can be applied to studies in which the target tissue has differential radiotracer retention from surrounding tissues.
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http://dx.doi.org/10.1089/thy.2017.0264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5672640PMC
November 2017

Risk Factors of I-Induced Salivary Gland Damage in Thyroid Cancer Patients.

J Clin Endocrinol Metab 2016 11 17;101(11):4085-4093. Epub 2016 Aug 17.

Department of Physiology and Cell Biology (B.H., S.M.J.), Human Cancer Genetics Program, Comprehensive Cancer Center (L.S., R.N., P.B., I.L.), Center for Biostatistics (X.Z., G.N.B.), Department of Internal Medicine, Division of Rheumatology and Immunology (W.J.), Department of Biomedical Informatics (X.Z., G.N.B., K.R.C.), Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism (R.K., M.D.R., J.S.), Department of Internal Medicine, Division of Oncology (M.D.R.), and Department of Otolaryngology-Head & Neck Surgery (R.C.), The Ohio State University, Columbus, Ohio 43210.

Context: Sialadenitis and xerostomia are major adverse effects of I therapy in thyroid cancer patients. The risk factors for these adverse effects, other than administered activity of I, have not been investigated.

Objective: The aim of this study is to identify risk factors for I-induced salivary gland damage among follicular cell-derived thyroid cancer patients.

Design: We enrolled 216 thyroid cancer patients who visited The Ohio State University Wexner Medical Center between April 2013 and April 2014. Symptoms of xerostomia and sialadenitis were identified via questionnaire and medical record search. To validate the findings in a large cohort, we retrospectively searched for ICD-9/10 codes for sialadenitis, xerostomia, and autoimmune disease associated with Sjögren's syndrome (AID-SS) in our existing database (n = 1507). Demographic and clinical information was extracted from medical records. Multivariate analyses were performed to identify independent predictors for salivary gland damage.

Results: I treatment associated with higher incidence of xerostomia and sialadenitis. Patients with xerostomia had 46 mCi higher mean cumulative I activity and 21 mCi higher mean first-administered I activity than patients without xerostomia. Increased age associated with higher incidence of xerostomia, and females had a higher incidence of sialadenitis. Patients who experienced sialadenitis before I therapy had higher sialadenitis incidence after I therapy. I-treated patients diagnosed with AID-SS, whether before or after I treatment, had a higher incidence of xerostomia and sialadenitis among I-treated patients.

Conclusion: Risk factors for I-induced salivary gland damage include administered I activity, age, gender, history of sialadenitis before I treatment, and AID-SS diagnosis.
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http://dx.doi.org/10.1210/jc.2016-1605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095242PMC
November 2016

Modulation of thyroidal radioiodide uptake by oncological pipeline inhibitors and Apigenin.

Oncotarget 2015 Oct;6(31):31792-804

Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH-43210, USA.

Targeted radioiodine therapy for thyroid cancer is based on selective stimulation of Na+/I- Symporter (NIS)-mediated radioactive iodide uptake (RAIU) in thyroid cells by thyrotropin. Patients with advanced thyroid cancer do not benefit from radioiodine therapy due to reduced or absent NIS expression. To identify inhibitors that can be readily translated into clinical care, we examined oncological pipeline inhibitors targeting Akt, MEK, PI3K, Hsp90 or BRAF in their ability to increase RAIU in thyroid cells expressing BRAFV600E or RET/PTC3 oncogene. Our data showed that (1) PI3K inhibitor GDC-0941 outperformed other inhibitors in RAIU increase mainly by decreasing iodide efflux rate to a great extent; (2) RAIU increase by all inhibitors was extensively reduced by TGF-β, a cytokine secreted in the invasive fronts of thyroid cancers; (3) RAIU reduction by TGF-β was mainly mediated by NIS reduction and could be reversed by Apigenin, a plant-derived flavonoid; and (4) In the presence of TGF-β, GDC-0941 with Apigenin co-treatment had the highest RAIU level in both BRAFV600E expressing cells and RET/PTC3 expressing cells. Taken together, Apigenin may serve as a dietary supplement along with small molecule inhibitors to improve radioiodine therapeutic efficacy on invasive tumor margins thereby minimizing future metastatic events.
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http://dx.doi.org/10.18632/oncotarget.5172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741640PMC
October 2015

microRNA-339-5p modulates Na+/I- symporter-mediated radioiodide uptake.

Endocr Relat Cancer 2015 Feb 17;22(1):11-21. Epub 2014 Nov 17.

Department of Physiology and Cell BiologyMolecularCellular and Developmental Biology Graduate Program, The Ohio State University, 1645 Neil Avenue, 304 Hamilton Hall, Columbus, Ohio 43210, USAGenomic MedicineDepartment of General, Transplant, and Liver Surgery, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warsaw, PolLaboratory of Human Cancer GeneticsCentre of New Technologies, CENT, University of Warsaw, 02-089 Warsaw, PolCenter for BiostatisticsThe Ohio State University, Columbus, Ohio, USA Department of Physiology and Cell BiologyMolecularCellular and Developmental Biology Graduate Program, The Ohio State University, 1645 Neil Avenue, 304 Hamilton Hall, Columbus, Ohio 43210, USAGenomic MedicineDepartment of General, Transplant, and Liver Surgery, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warsaw, PolLaboratory of Human Cancer GeneticsCentre of New Technologies, CENT, University of Warsaw, 02-089 Warsaw, PolCenter for BiostatisticsThe Ohio State University, Columbus, Ohio, USA

Na(+)/I(-) symporter (NIS)-mediated radioiodide uptake (RAIU) serves as the basis for targeted ablation of thyroid cancer remnants. However, many patients with thyroid cancer have reduced NIS expression/function and hence do not benefit from radioiodine therapy. microRNA (miR) has emerged as a promising therapeutic target in many diseases; yet, the role of miRs in NIS-mediated RAIU has not been investigated. In silico analysis was used to identify miRs that may bind to the 3'UTR of human NIS (hNIS). The top candidate miR-339-5p directly bound to the 3'UTR of hNIS. miR-339-5p overexpression decreased NIS-mediated RAIU in HEK293 cells expressing exogenous hNIS, decreased the levels of NIS mRNA, and RAIU in transretinoic acid/hydrocortisone (tRA/H)-treated MCF-7 human breast cancer cells as well as thyrotropin-stimulated PCCl3 rat thyroid cells. Nanostring nCounter rat miR expression assay was conducted to identify miRs deregulated by TGFβ, Akti-1/2, or 17-AAG known to modulate RAIU in PCCl3 cells. Among 38 miRs identified, 18 were conserved in humans. One of the 18 miRs, miR-195, was predicted to bind to the 3'UTR of hNIS and its overexpression decreased RAIU in tRA/H-treated MCF-7 cells. miR-339-5p was modestly increased in most papillary thyroid carcinomas (PTCs), yet miR-195 was significantly decreased in PTCs. Interestingly, the expression profiles of 18 miRs could be used to distinguish most PTCs from nonmalignant thyroid tissues. This is the first report, to our knowledge, demonstrating that hNIS-mediated RAIU can be modulated by miRs, and that the same miRs may also play roles in the development or maintenance of thyroid malignancy. Accordingly, miRs may serve as emerging targets to halt the progression of thyroid cancer and to enhance the efficacy of radioiodine therapy.
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http://dx.doi.org/10.1530/ERC-14-0439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4298451PMC
February 2015

Modulation of sodium iodide symporter in thyroid cancer.

Horm Cancer 2014 Dec 19;5(6):363-73. Epub 2014 Sep 19.

Department of Physiology and Cell Biology, The Ohio State University, 1645 Neil Avenue, 304 Hamilton Hall, Columbus, OH, 43210, USA.

Radioactive iodine (RAI) is a key therapeutic modality for thyroid cancer. Loss of RAI uptake in thyroid cancer inversely correlates with patient's survival. In this review, we focus on the challenges encountered in delivering sufficient doses of I-131 to eradicate metastatic lesions without increasing the risk of unwanted side effects. Sodium iodide symporter (NIS) mediates iodide influx, and NIS expression and function can be selectively enhanced in thyroid cells by thyroid-stimulating hormone. We summarize our current knowledge of NIS modulation in normal and cancer thyroid cells, and we propose that several reagents evaluated in clinical trials for other diseases can be used to restore or further increase RAI accumulation in thyroid cancer. Once validated in preclinical mouse models and clinical trials, these reagents, mostly small-molecule inhibitors, can be readily translated into clinical practice. We review available genetically engineered mouse models of thyroid cancer in terms of their tumor development and progression as well as their thyroid function. These mice will not only provide important insights into the mechanisms underlying the loss of RAI uptake in thyroid tumors but will also serve as preclinical animal models to evaluate the efficacy of candidate reagents to selectively increase RAI uptake in thyroid cancers. Taken together, we anticipate that the optimal use of RAI in the clinical management of thyroid cancer is yet to come in the near future.
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http://dx.doi.org/10.1007/s12672-014-0203-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458071PMC
December 2014

Quantitative characterization of cell behaviors through cell cycle progression via automated cell tracking.

PLoS One 2014 9;9(6):e98762. Epub 2014 Jun 9.

Precision Measurement and Control Laboratory, Department of Mechanical and Aerospace Engineering, The Ohio State University, Columbus, Ohio, United States of America.

Cell behaviors are reflections of intracellular tension dynamics and play important roles in many cellular processes. In this study, temporal variations in cell geometry and cell motion through cell cycle progression were quantitatively characterized via automated cell tracking for MCF-10A non-transformed breast cells, MCF-7 non-invasive breast cancer cells, and MDA-MB-231 highly metastatic breast cancer cells. A new cell segmentation method, which combines the threshold method and our modified edge based active contour method, was applied to optimize cell boundary detection for all cells in the field-of-view. An automated cell-tracking program was implemented to conduct live cell tracking over 40 hours for the three cell lines. The cell boundary and location information was measured and aligned with cell cycle progression with constructed cell lineage trees. Cell behaviors were studied in terms of cell geometry and cell motion. For cell geometry, cell area and cell axis ratio were investigated. For cell motion, instantaneous migration speed, cell motion type, as well as cell motion range were analyzed. We applied a cell-based approach that allows us to examine and compare temporal variations of cell behavior along with cell cycle progression at a single cell level. Cell body geometry along with distribution of peripheral protrusion structures appears to be associated with cell motion features. Migration speed together with motion type and motion ranges are required to distinguish the three cell-lines examined. We found that cells dividing or overlapping vertically are unique features of cell malignancy for both MCF-7 and MDA-MB-231 cells, whereas abrupt changes in cell body geometry and cell motion during mitosis are unique to highly metastatic MDA-MB-231 cells. Taken together, our live cell tracking system serves as an invaluable tool to identify cell behaviors that are unique to malignant and/or highly metastatic breast cancer cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0098762PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049640PMC
June 2015

Apigenin in combination with Akt inhibition significantly enhances thyrotropin-stimulated radioiodide accumulation in thyroid cells.

Thyroid 2014 May 6;24(5):878-87. Epub 2014 Mar 6.

1 Molecular, Cellular and Developmental Biology Graduate Program, The Ohio State University , Columbus, Ohio.

Background: Selectively increased radioiodine accumulation in thyroid cells by thyrotropin (TSH) allows targeted treatment of thyroid cancer. However, the extent of TSH-stimulated radioiodine accumulation in some thyroid tumors is not sufficient to confer therapeutic efficacy. Hence, it is of clinical importance to identify novel strategies to selectively further enhance TSH-stimulated thyroidal radioiodine accumulation.

Methods: PCCl3 rat thyroid cells, PCCl3 cells overexpressing BRAF(V600E), or primary cultured tumor cells from a thyroid cancer mouse model, under TSH stimulation were treated with various reagents for 24 hours. Cells were then subjected to radioactive iodide uptake, kinetics, efflux assays, and protein extraction followed by Western blotting against selected antibodies.

Results: We previously reported that Akt inhibition increased radioiodine accumulation in thyroid cells under chronic TSH stimulation. Here, we identified Apigenin, a plant-derived flavonoid, as a reagent to further enhance the iodide influx rate increased by Akt inhibition in thyroid cells under acute TSH stimulation. Akt inhibition is permissive for Apigenin's action, as Apigenin alone had little effect. This action of Apigenin requires p38 MAPK activity but not PKC-δ. The increase in radioiodide accumulation by Apigenin with Akt inhibition was also observed in thyroid cells expressing BRAF(V600E) and in primary cultured thyroid tumor cells from TRβ(PV/PV) mice.

Conclusion: Taken together, Apigenin may serve as a dietary supplement in combination with Akt inhibitors to enhance therapeutic efficacy of radioiodine for thyroid cancer.
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http://dx.doi.org/10.1089/thy.2013.0614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4026312PMC
May 2014

Real-time visual sensing system achieving high-speed 3D particle tracking with nanometer resolution.

Appl Opt 2013 Nov;52(31):7530-9

This paper presents a real-time visual sensing system, which is created to achieve high-speed three-dimensional (3D) motion tracking of microscopic spherical particles in aqueous solutions with nanometer resolution. The system comprises a complementary metal-oxide-semiconductor (CMOS) camera, a field programmable gate array (FPGA), and real-time image processing programs. The CMOS camera has high photosensitivity and superior SNR. It acquires images of 128×120 pixels at a frame rate of up to 10,000 frames per second (fps) under the white light illumination from a standard 100 W halogen lamp. The real-time image stream is downloaded from the camera directly to the FPGA, wherein a 3D particle-tracking algorithm is implemented to calculate the 3D positions of the target particle in real time. Two important objectives, i.e., real-time estimation of the 3D position matches the maximum frame rate of the camera and the timing of the output data stream of the system is precisely controlled, are achieved. Two sets of experiments were conducted to demonstrate the performance of the system. First, the visual sensing system was used to track the motion of a 2 μm polystyrene bead, whose motion was controlled by a three-axis piezo motion stage. The ability to track long-range motion with nanometer resolution in all three axes is demonstrated. Second, it was used to measure the Brownian motion of the 2 μm polystyrene bead, which was stabilized in aqueous solution by a laser trapping system.
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http://dx.doi.org/10.1364/AO.52.007530DOI Listing
November 2013

Ernest L. Mazzaferri, MD, MACP (1936-2013).

Thyroid 2013 Aug;23(8):917-23

Department of Endocrinology, Veracyte, Inc., South San Francisco, California, USA.

Professor and physician Dr. Ernest L. Mazzaferri Sr. passed away on May 14, 2013, at 76 years of age ( 1 , 2 ). Ernie is remembered as a caring and talented physician, an accomplished scholar and educator, as well as a loving husband, father, and grandfather. He was a luminary figure, and few people have had a greater impact in thyroidology in recent decades. Here we include reflections from a few of us that knew him, as well as commentaries from people who did not. Ernie's passion was caring for patients and how to improve their care. Our goal is to pay tribute and memorialize the person we knew and the impact that he had on patients around the world through his dedication to research, lecturing, and writing that achieved remarkable global influence.
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http://dx.doi.org/10.1089/thy.2013.2308.obDOI Listing
August 2013

Modulation of sodium/iodide symporter expression in the salivary gland.

Thyroid 2013 Aug 17;23(8):1029-36. Epub 2013 Jul 17.

Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA.

Background: Physiologic iodide-uptake, mediated by the sodium/iodide symporter (NIS), in the salivary gland confers its susceptibility to radioactive iodine-induced damage following (131)I treatment of thyroid cancer. Subsequent quality of life for thyroid cancer survivors can be decreased due to recurrent sialoadenitis and persistent xerostomia. NIS expression at the three principal salivary duct components in various pathological conditions was examined to better our understanding of NIS modulation in the salivary gland.

Methods: NIS expression was evaluated by immunohistochemistry in human salivary gland tissue microarrays constructed of normal, inflamed, and neoplastic salivary tissue cores. Cumulative (123)I radioactivity reflecting the combination of NIS activity with clearance of saliva secretion in submandibular and parotid salivary glands was evaluated by single-photon emission computed tomography/computed tomography imaging 24 hours after (123)I administration in 50 thyroid cancer patients.

Results: NIS is highly expressed in the basolateral membranes of the majority of striated ducts, yet weakly expressed in few intercalated and excretory duct cells. The ratio of (123)I accumulation between parotid and submandibular glands is 2.38±0.19. However, the corresponding ratio of (123)I accumulation normalized by volume of interest is 1.19±0.06. The percentage of NIS-positive striated duct cells in submandibular salivary glands was statistically greater than in parotid salivary glands, suggesting a higher clearance rate of saliva secretion in submandibular salivary glands. NIS expression in striated ducts was heterogeneously decreased or absent in sialoadenitis. Most ductal salivary gland tumors did not express NIS. However, Warthin's tumors of striated duct origin exhibited consistent and intense NIS staining, corresponding with radioactive iodine uptake.

Conclusions: NIS expression is tightly modulated during the transition of intercalated to striated ducts and striated to excretory ducts in salivary ductal cells. NIS expression in salivary glands is decreased during inflammation and tumor formation. Further investigation may identify molecular targets and/or pharmacologic agents that allow selective inhibition of NIS expression/activity in salivary glands during radioactive iodine treatment.
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http://dx.doi.org/10.1089/thy.2012.0571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3752512PMC
August 2013

MEK inhibition leads to lysosome-mediated Na+/I- symporter protein degradation in human breast cancer cells.

Endocr Relat Cancer 2013 Apr 22;20(2):241-50. Epub 2013 Mar 22.

Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH 43210, USA.

The Na(+)/I(-) symporter (NIS (SLC5A5)) is a transmembrane glycoprotein that mediates active iodide uptake into thyroid follicular cells. NIS-mediated iodide uptake in thyroid cells is the basis for targeted radionuclide imaging and treatment of differentiated thyroid carcinomas and their metastases. Furthermore, NIS is expressed in many human breast tumors but not in normal non-lactating breast tissue, suggesting that NIS-mediated radionuclide uptake may also allow the imaging and targeted therapy of breast cancer. However, functional cell surface NIS expression is often low in breast cancer, making it important to uncover signaling pathways that modulate NIS expression at multiple levels, from gene transcription to posttranslational processing and cell surface trafficking. In this study, we investigated NIS regulation in breast cancer by MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK) signaling, an important cell signaling pathway involved in oncogenic transformation. We found that MEK inhibition decreased NIS protein levels in all-trans retinoic acid/hydrocortisone-treated MCF-7 cells as well as human breast cancer cells expressing exogenous NIS. The decrease in NIS protein levels by MEK inhibition was not accompanied by a decrease in NIS mRNA or a decrease in NIS mRNA export from the nucleus to the cytoplasm. NIS protein degradation upon MEK inhibition was prevented by lysosome inhibitors but not by proteasome inhibitors. Interestingly, NIS protein level was correlated with MEK/ERK activation in human breast tumors from a tissue microarray. Taken together, MEK activation appears to play an important role in maintaining NIS protein stability in human breast cancers.
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http://dx.doi.org/10.1530/ERC-12-0342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837521PMC
April 2013

Efficient delivery of cyclic peptides into mammalian cells with short sequence motifs.

ACS Chem Biol 2013 Feb 12;8(2):423-31. Epub 2012 Nov 12.

Department of Chemistry and Biochemistry and Ohio State Biochemistry Program, The Ohio State University , 100 West 18th Avenue, Columbus, Ohio 43210, USA.

Cyclic peptides hold great potential as therapeutic agents and research tools, but their broad application has been limited by poor membrane permeability. Here, we report a potentially general approach for intracellular delivery of cyclic peptides. Short peptide motifs rich in arginine and hydrophobic residues (e.g., FΦRRRR, where Φ is l-2-naphthylalanine), when embedded into small- to medium-sized cyclic peptides (7-13 amino acids), bound to the plasma membrane of mammalian cultured cells and were subsequently internalized by the cells. Confocal microscopy and a newly developed peptide internalization assay demonstrated that cyclic peptides containing these transporter motifs were translocated into the cytoplasm and nucleus at efficiencies 2-5-fold higher than that of nonaarginine (R(9)). Furthermore, incorporation of the FΦRRRR motif into a cyclic peptide containing a phosphocoumaryl aminopropionic acid (pCAP) residue generated a cell permeable, fluorogenic probe for detecting intracellular protein tyrosine phosphatase activities.
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http://dx.doi.org/10.1021/cb3005275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3574231PMC
February 2013

Micro-single-photon emission computed tomography image acquisition and quantification of sodium-iodide symporter-mediated radionuclide accumulation in mouse thyroid and salivary glands.

Thyroid 2012 Jun 27;22(6):617-24. Epub 2012 Apr 27.

Molecular, Cellular, and Developmental Biology Graduate Program, Department of Physiology and Cell Biology, The Ohio State University, 1645 Neil Ave., Columbus, OH 43210, USA.

Background: Micro-single-photon emission computed tomography (SPECT) provides a noninvasive way to evaluate the effects of genetic and/or pharmacological modulation on sodium-iodide symporter (NIS)-mediated radionuclide accumulation in mouse thyroid and salivary glands. However, parameters affecting image acquisition and analysis of mouse thyroids and salivary glands have not been thoroughly investigated. In this study, we investigated the effects of region-of-interest (ROI) selection, collimation, scan time, and imaging orbit on image acquisition and quantification of thyroidal and salivary radionuclide accumulation in mice.

Methods: The effects of data window minima and maxima on thyroidal and salivary ROI selection using a visual boundary method were examined in SPECT images acquired from mice injected with (123)I NaI. The effects of collimation, scan time, and imaging orbit on counting linearity and signal intensity were investigated using phantoms filled with various activities of (123)I NaI or Tc-99m pertechnetate. Spatial resolution of target organs in whole-animal images was compared between circular orbit with parallel-hole collimation and spiral orbit with five-pinhole collimation. Lastly, the inter-experimental variability of the same mouse scanned multiple times was compared with the intra-experimental variability among different mice scanned at the same time.

Results: Thyroid ROI was separated from salivary glands by empirically increasing the data window maxima. Counting linearity within the range of 0.5-14.2 μCi was validated by phantom imaging using single- or multiple-pinhole collimators with circular or spiral imaging orbit. Scanning time could be shortened to 15 minutes per mouse without compromising counting linearity despite proportionally decreased signal intensity. Whole-animal imaging using a spiral orbit with five-pinhole collimators achieved a high spatial resolution and counting linearity. Finally, the extent of inter-experimental variability of NIS-mediated radionuclide accumulation in the thyroid and salivary glands by SPECT imaging in the same mouse was less than the magnitude of variability among the littermates.

Conclusions: The impacts of multiple variables and experimental designs on micro-SPECT imaging and quantification of radionuclide accumulation in mouse thyroid and salivary glands can be minimized. This platform will serve as an invaluable tool to screen for pharmacologic reagents that differentially modulate thyroidal and salivary radioiodine accumulation in preclinical mouse models.
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http://dx.doi.org/10.1089/thy.2011.0348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3358108PMC
June 2012

Modulation of sodium iodide symporter expression and function by LY294002, Akti-1/2 and Rapamycin in thyroid cells.

Endocr Relat Cancer 2012 Jun 3;19(3):291-304. Epub 2012 May 3.

The Ohio State Biochemistry Program, The Ohio State University, 304 Hamilton Hall, 1645 Neil Avenue, Columbus, Ohio 43210, USA.

The selective increase of Na(+)/I(-) symporter (NIS)-mediated active iodide uptake in thyroid cells allows the use of radioiodine I(131) for diagnosis and targeted treatment of thyroid cancers. However, NIS-mediated radioiodine accumulation is often reduced in thyroid cancers due to decreased NIS expression/function. As PI3K signaling is overactivated in many thyroid tumors, we investigated the effects of inhibitors for PI3K, Akt, or mTORC1 as well as their interplay on NIS modulation in thyroid cells under chronic TSH stimulation. PI3K inhibition by LY294002 increased NIS-mediated radioiodide uptake (RAIU) mainly through upregulation of NIS expression, however, mTORC1 inhibition by Rapamycin did not increase NIS-mediated RAIU despite increased NIS protein levels. In comparison, Akt inhibition by Akti-1/2 did not increase NIS protein levels, yet markedly increased NIS-mediated RAIU by decreasing iodide efflux rate and increasing iodide transport rate and iodide affinity of NIS. The effects of Akti-1/2 on NIS-mediated RAIU are not detected in nonthyroid cells, implying that Akti-1/2 or its derivatives may represent potential pharmacological reagents to selectively increase thyroidal radioiodine accumulation and therapeutic efficacy.
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http://dx.doi.org/10.1530/ERC-11-0288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736852PMC
June 2012

Microarray analysis of genes associated with cell surface NIS protein levels in breast cancer.

BMC Res Notes 2011 Oct 11;4:397. Epub 2011 Oct 11.

Integrated Biomedical Sciences Graduate Program, The Ohio State University, Columbus, Ohio 43210, USA.

Background: Na+/I- symporter (NIS)-mediated iodide uptake allows radioiodine therapy for thyroid cancer. NIS is also expressed in breast tumors, raising potential for radionuclide therapy of breast cancer. However, NIS expression in most breast cancers is low and may not be sufficient for radionuclide therapy. We aimed to identify biomarkers associated with NIS expression such that mechanisms underlying NIS modulation in human breast tumors may be elucidated.

Methods: Published oligonucleotide microarray data within the National Center for Biotechnology Information Gene Expression Omnibus database were analyzed to identify gene expression tightly correlated with NIS mRNA level among human breast tumors. NIS immunostaining was performed in a tissue microarray composed of 28 human breast tumors which had corresponding oligonucleotide microarray data available for each tumor such that gene expression associated with cell surface NIS protein level could be identified.

Results And Discussion: NIS mRNA levels do not vary among breast tumors or when compared to normal breast tissues when detected by Affymetrix oligonucleotide microarray platforms. Cell surface NIS protein levels are much more variable than their corresponding NIS mRNA levels. Despite a limited number of breast tumors examined, our analysis identified cysteinyl-tRNA synthetase as a biomarker that is highly associated with cell surface NIS protein levels in the ER-positive breast cancer subtype.

Conclusions: Further investigation on genes associated with cell surface NIS protein levels within each breast cancer molecular subtype may lead to novel targets for selectively increasing NIS expression/function in a subset of breast cancers patients.
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http://dx.doi.org/10.1186/1756-0500-4-397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205061PMC
October 2011

Single photon emission computed tomography imaging for temporal dynamics of thyroidal and salivary radionuclide accumulation in 17-allyamino-17-demothoxygeldanamycin-treated thyroid cancer mouse model.

Endocr Relat Cancer 2011 Feb 30;18(1):27-37. Epub 2010 Nov 30.

The Ohio State Biochemistry Program, The Ohio State University, Columbus, Ohio 43210, USA.

Selective iodide uptake and prolonged iodine retention in the thyroid is the basis for targeted radioiodine therapy for thyroid cancer patients; however, salivary gland dysfunction is the most frequent nonthyroidal complications. In this study, we have used noninvasive single photon emission computed tomography functional imaging to quantify the temporal dynamics of thyroidal and salivary radioiodine accumulation in mice. At 60  min post radionuclide injection, radionuclide accumulation in the salivary gland was generally higher than that in thyroid due to much larger volume of the salivary gland. However, radionuclide accumulation per anatomic unit in the salivary gland was lower than that in thyroid and was comparable among mice of different age and gender. Differently, radionuclide accumulation per anatomic unit in thyroid varied greatly among mice. The extent of thyroidal radioiodine accumulation stimulated by a single dose of exogenous bovine TSH (bTSH) in triiodothyronine (T₃)-supplemented mice was much less than that in mice received neither bTSH nor T₃ (nontreated mice), suggesting that the duration of elevated serum TSH level is important to maximize thyroidal radioiodine accumulation. Furthermore, the extent and duration of radioiodine accumulation stimulated by bTSH was less in the thyroids of the thyroid-targeted RET/PTC1 (thyroglobulin (Tg)-PTC1) mice bearing thyroid tumors compared with the thyroids in wild-type (WT) mice. Finally, the effect of 17-allyamino-17-demothoxygeldanamycin on increasing thyroidal, but not salivary, radioiodine accumulation was validated in both WT mice and Tg-PTC1 preclinical thyroid cancer mouse model.
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http://dx.doi.org/10.1677/ERC-10-0185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3902865PMC
February 2011

Three-axis rapid steering of optically propelled micro/nanoparticles.

Rev Sci Instrum 2009 Jun;80(6):063107

Department of Mechanical Engineering, The Ohio State University, 201 West 19th Avenue, Columbus, Ohio 43210, USA.

This paper presents the design and implementation of a three-axis steering system, wherein a micro/nanoparticle is optically trapped and propelled to serve as a measurement probe. The actuators in the system consist of a deformable mirror enabling axial steering and a two-axis acousto-optic deflector for lateral steering. The actuation range is designed and calibrated to be over 20 microm along the two lateral axes and over 10 microm along the axial direction. The actuation bandwidth of the two lateral axes is over 50 kHz and the associated resolution is 0.016 nm (1sigma). The axial resolution is 0.16 nm, while the bandwidth is enhanced to over 3 kHz by model cancellation method. The performance of the three-axis steering system is illustrated by three sets of experiments. First, active Brownian motion control of the trapped probe is utilized to enhance trapping stability. Second, a large range three-dimensional (3D) steering of a 1.87 microm probe, contouring a complex 3D trajectory in a 6 x 6 x 4 microm3 volume, is demonstrated. Third, a closed-loop steering is implemented to achieve improved precision.
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http://dx.doi.org/10.1063/1.3156838DOI Listing
June 2009

Two-axis probing system for atomic force microscopy.

Rev Sci Instrum 2008 Feb;79(2 Pt 1):023705

Department of Mechanical Engineering, The Ohio State University, Columbus, Ohio 43210, USA.

A novel two-axis probing system is proposed for multiaxis atomic force microscopy (AFM). It employs a compliant manipulator that is optimally designed in terms of geometries and kinematics, and is actuated by multiple magnetic actuators to simultaneously control tip position and change tip orientation to achieve greater accessibility of the sample surface when imaging surfaces having large geometric variations. It leads to the creation of a multiaxis AFM system, which is a three-dimensional surface tool rather than a two-dimensional planar surface tool. The use of the system to scan the bottom corner of a grating step is reported.
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http://dx.doi.org/10.1063/1.2841805DOI Listing
February 2008

Creation and characterization of a doxycycline-inducible mouse model of thyroid-targeted RET/PTC1 oncogene and luciferase reporter gene coexpression.

Thyroid 2007 Dec;17(12):1181-8

Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210, USA.

Background: RET/PTC1 chromosomal rearrangement is associated with papillary thyroid carcinoma formation in children exposed to ionizing radiation. We previously created a transgenic mouse model with thyroid-targeted constitutive RET/PTC1 expression and demonstrated papillary thyroid carcinoma formation.

Objective: In this study, we aimed to create a doxycycline-inducible mouse model of thyroid RET/PTC1 and luciferase reporter gene coexpression to allow for noninvasive monitoring of transgene expression in mice of various ages and timepoints after induction.

Design: Transgenic mice carrying the rtTA gene driven by the thyroglobulin promoter were generated, and crossed with responder mice carrying RET/PTC1 and firefly luciferase genes under control of a bidirectional tetracycline response element.

Main Outcomes: Most bitransgenic mice had thyroid-targeted, doxycycline-independent transgene expression. Only one line had thyroid-targeted, doxycycline-regulated RET/PTC1 and luciferase coexpression, in which doxycycline induction of RET/PTC1 led to Erk phosphorylation and reduced expression of the sodium/iodide symporter (NIS). However, thyroid lesions were not found in any bitransgenic mice examined.

Conclusions: We found that acute RET/PTC1 expression can activate the MEK/Erk pathway and downregulate NIS expression in the mouse thyroid gland. However, a higher level of RET/PTC1 is likely necessary for tumor formation. Thyroid luciferase induction was detectable noninvasively using IVIS in vivo imaging.
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http://dx.doi.org/10.1089/thy.2007.0224DOI Listing
December 2007

Identification of in vivo phosphorylation sites and their functional significance in the sodium iodide symporter.

J Biol Chem 2007 Dec 3;282(51):36820-8. Epub 2007 Oct 3.

Integrated Biomedical Science Graduate Program, Department of Physiology and Cell Biology, Ohio State University, Columbus 43210, USA.

The Na+/I- symporter (NIS)-mediated iodide uptake activity is the basis for targeted radioiodide ablation of thyroid cancers. Although it has been shown that NIS protein is phosphorylated, neither the in vivo phosphorylation sites nor their functional significance has been reported. In this study, Ser-43, Thr-49, Ser-227, Thr-577, and Ser-581 were identified as in vivo NIS phosphorylation sites by mass spectrometry. Kinetic analysis of NIS mutants of the corresponding phosphorylated amino acid residue indicated that the velocity of iodide transport of NIS is modulated by the phosphorylation status of Ser-43 and Ser-581. We also found that the phosphorylation status of Thr-577 may be important for NIS protein stability and that the phosphorylation status of Ser-227 is functionally silent. Thr-49 appears to be critical for proper local structure/conformation of NIS because mutation of Thr-49 to alanine, aspartic acid, or serine results in reduced NIS activity without alterations in total or cell surface NIS protein levels. Taken together, we showed that NIS protein levels and functional activity could be modulated by phosphorylation through distinct mechanisms.
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http://dx.doi.org/10.1074/jbc.M706817200DOI Listing
December 2007

PI3K activation is associated with intracellular sodium/iodide symporter protein expression in breast cancer.

BMC Cancer 2007 Jul 25;7:137. Epub 2007 Jul 25.

Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210, USA.

Background: The sodium/iodide symporter (NIS) is a membrane glycoprotein mediating active iodide uptake in the thyroid gland and is the molecular basis for radioiodide imaging and therapeutic ablation of thyroid carcinomas. NIS is expressed in the lactating mammary gland and in many human breast tumors, raising interest in similar use for diagnosis and treatment. However, few human breast tumors have clinically evident iodide uptake ability. We previously identified PI3K signaling as important in NIS upregulation in transgenic mouse models of breast cancer, and the PI3K pathway is commonly activated in human breast cancer.

Methods: NIS expression, subcellular localization, and function were analyzed in MCF-7 human breast cancer cells and MCF-7 cells stably or transiently expressing PI3K p110alpha subunit using Western blot of whole cell lysate, cell surface biotinylation Western blot and immunofluorescence, and radioiodide uptake assay, respectively. NIS localization was determined in a human breast cancer tissue microarray using immunohistochemical staining (IHC) and was correlated with pre-existing pAkt IHC data. Statistical analysis consisted of Student's t-test (in vitro studies) or Fisher's Exact Test (in vivo correlational studies).

Results: In this study, we demonstrate that PI3K activation in MCF-7 human mammary carcinoma cells leads to expression of underglycosylated NIS lacking cell surface trafficking necessary for iodide uptake ability. PI3K activation also appears to interfere with cell surface trafficking of exogenous NIS as well as all-trans retinoic acid-induced endogenous NIS. A correlation between NIS expression and upregulation of PI3K signaling was found in a human breast cancer tissue microarray.

Conclusion: Thus, the PI3K pathway likely plays a major role in the discordance between NIS expression and iodide uptake in breast cancer patients. Further study is warranted to realize the application of NIS-mediated radioiodide ablation in breast cancer.
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http://dx.doi.org/10.1186/1471-2407-7-137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1963336PMC
July 2007

MEK signaling modulates sodium iodide symporter at multiple levels and in a paradoxical manner.

Endocr Relat Cancer 2007 Jun;14(2):421-32

Integrated Biomedical Science Graduate Program, The Ohio State University, Columbus, Ohio 43210, USA.

The Na(+)/I(-) symporter (NIS)-mediated iodide uptake is the basis for targeted radioiodine ablation of thyroid cancers. However, NIS-mediated radioiodide uptake (RAIU) activity is often reduced in thyroid cancers. As mitogen activated protein kinase (MAPK) signaling pathway is activated in about 70% of papillary thyroid carcinoma, we investigated whether MEK (MAPK kinase) inhibition will restore NIS protein levels and NIS-mediated RAIU activity in RET/PTC oncogene-transformed thyroid cells. We found that MEK inhibitor PD98059 increased NIS protein levels within 30 min of treatment. However, the increase of NIS protein level was not accompanied with an increase in NIS-mediated RAIU activity, particularly at early time points of PD98059 treatment. PD98059 also decreased RAIU activity mediated by exogenous NIS in non-thyroid cells. The transient decrease of RAIU activity by PD98059 in thyroid cells was not due to decreased NIS cell surface level, decreased NIS binding affinity for I(-) , or increased iodide efflux. While PD98059 moderately decreased Na(+)/K(+)-ATPase activity, ouabain titration indicates that the extent of decrease in Na(+)/K(+)-ATPase activity is much greater than the extent of decrease in RAIU activity. Additionally, a decrease of Na(+)/K(+)-ATPase activity was not accompanied with a decrease of biotin uptake activity mediated by Na(+)-dependent multivitamin transporter. Since PD98059 reduced V(max)- I(-) without decreasing NIS cell surface levels, it is most likely that PD98059 decreases the turnover rate of iodide transport with an yet to be identified mechanism.
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http://dx.doi.org/10.1677/erc.1.01263DOI Listing
June 2007