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Jhiang, Smanik
Correlation of Na+/I- symporter expression and activity: implications of Na+/I- symporter as an imaging reporter gene.Vadysirisack DD, Shen DH, Jhiang SM. J Nucl Med. 2006 Jan;47(1):182-90.
"The Na(+)/I(-) symporter (NIS) has been proposed as an imaging reporter gene to ascertain the expression of therapeutic genes in targeted tissues. In this study, we investigated whether posttranslational processing and cell-surface trafficking of NIS affect NIS-mediated radioiodide uptake in cells expressing exogenous NIS.
METHODS: We established FTC133, HeLa, and PC12 cell lines with doxycycline-inducible NIS expression to investigate the correlation among total NIS protein levels, cell-surface NIS protein levels, and NIS-mediated radioiodide uptake in cells induced with various levels of NIS.
RESULTS: We found that most exogenous NIS proteins were efficiently trafficked to the cell surface; thus, a possible deficiency in NIS cell-surface trafficking is not a concern for clinical applications of NIS gene transfer. The extent of radioiodide uptake correlated with cell-surface NIS protein level within a certain range, suggesting that the imaging signals can quantify levels of NIS expression only within a certain range in vivo. Finally, a moderate increase in NIS protein level significantly increased radioiodide uptake, indicating that a low level of NIS expression is sufficient to facilitate radionuclide imaging in vivo.
CONCLUSION: Our study suggests that NIS will be useful as an imaging reporter gene to ascertain that the therapeutic gene is localized to the correct tissue and to monitor the expression levels and duration of the therapeutic gene."
Expression of sodium iodide symporter in the lacrimal drainage system: implication for the mechanism underlying nasolacrimal duct obstruction in I(131)-treated patients.Morgenstern KE, Vadysirisack DD, Zhang Z, Cahill KV, Foster JA, Burns JA, Kloos RT, Jhiang SM. Ophthal Plast Reconstr Surg. 2005 Sep;21(5):337-44. [abstract only]
"PURPOSE: Nasolacrimal outflow obstruction has been associated with high-dose (>150 mCi) radioactive iodine (I(131)) treatment. Commonly used for thyroid cancer treatment, I(131) is effectively transported in the targeted tissue by the Na(+)/I symporter (NIS). We hypothesized that NIS is expressed in the lacrimal sac and nasolacrimal duct and that active accumulation of I(131) is responsible for the clinical observations seen in these patients.
METHODS: Reverse transcriptase-polymerase chain reaction and immunohistochemical analyses were used to evaluate NIS expression in both archived and fresh human tissues
RESULTS: Reverse transcriptase-polymerase chain reaction analysis showed that NIS mRNA is present in the lacrimal sac. Immunohistochemical analysis indicated that NIS protein is expressed in the stratified columnar epithelial cells of the lacrimal sac and nasolacrimal duct. NIS protein was undetectable in the lacrimal gland, Wolfring and Krause glands, conjunctiva, canaliculus, and nasal mucosa. NIS-expressing columnar epithelial cells were absent and fibrosis was evident in the lacrimal sacs from I(131)-treated patients undergoing dacryocystorhinostomy.
CONCLUSIONS: NIS is present in the lacrimal sac and nasolacrimal duct of humans, correlating to the anatomic areas of clinical obstruction that develop in patients treated with greater than 150 mCi of I(131). This suggests that NIS may be the vector of radiation-induced injury to the lacrimal system. To our knowledge, this is the first report of any ion transporter in the nasolacrimal outflow system and raises new questions as to the role the lacrimal sac plays in the modification of tears and in lacrimal outflow pathology."
Cell surface targeting accounts for the difference in iodide uptake activity between human Na+/I- symporter and rat Na+/I- symporter.Zhang Z, Liu YY, Jhiang SM. J Clin Endocrinol Metab. 2005 Nov;90(11):6131-40. Epub 2005 Aug 16.
"CONTEXT: The Na+/I- symporter (NIS) has been proposed to serve as an imaging reporter gene to optimize vector delivery, monitor therapeutic gene expression, and map the tissue/organ sites of repopulated progenitor cells in vivo. In addition, NIS can serve as a therapeutic gene to facilitate targeted radionuclide therapy for various cancers.
OBJECTIVE: It was reported that rat NIS (rNIS) confers higher radioactive iodide uptake (RAIU) activity than human NIS (hNIS). We aim to investigate the mechanism underlying this difference.
RESULTS: We showed that the open reading frames (ORF) of hNIS and rNIS, although encoding for proteins with 83% amino acid identity, exhibit a significant difference in RAIU activity in transfected cells. The ORF rNIS confers four to five times higher RAIU activity as well as cell surface NIS accumulation than ORF hNIS despite similar total NIS protein levels. Multiple regions appear to play roles in the difference in NIS cell surface levels between ORF hNIS and ORF rNIS, indicating that proper folding of NIS in tertiary structure is critical for NIS cell surface targeting. We also showed that the kinetics of Na+ binding are different between ORF hNIS and ORF rNIS, and that site-directed mutation changing Ser200 to other uncharged amino acid significantly increased RAIU activity in ORF hNIS.
CONCLUSIONS: NIS transgene could be optimized for
cell surface trafficking and RAIU activity to improve its clinical
applications."
Forskolin, 8-Br-3',5'-cyclic adenosine 5'-monophosphate, and catalytic protein kinase A expression in the nucleus increase radioiodide uptake and sodium/iodide symporter protein levels in RET/PTC1-expressing cells.Venkateswaran A, Marsee DK, Green SH, Jhiang SM. J Clin Endocrinol Metab. 2004 Dec;89(12):6168-72.
"RET/PTC1, a
thyroid-specific oncogene, has been reported to down-regulate
sodium/iodide symporter (NIS) expression and function in vitro and in
vivo. Recently, RET/PTC1 has been shown to interfere with TSH
signaling at multiple levels in thyroid cells. The objective of this
study was to investigate whether RET/PTC1-mediated NIS reduction can
be rescued by activating cAMP-protein kinase A (PKA) pathways. We
showed that both forskolin and 8-Br-cAMP increase radioiodide uptake
and NIS protein in RET/PTC1-expressing cells to the same extent as the
parental PC Cl 3 cells. We found that RET/PTC1 decreases nuclear
localization of catalytic PKA, and forskolin treatment was able to
counteract this RET/PTC1 effect. Furthermore, transient expression of
catalytic PKA in the nucleus increased radioiodide uptake and NIS
protein in RET/PTC1-expressing cells. Taken together, these studies
suggest that RET/PTC1 down-regulates NIS expression by interrupting
TSH/cAMP signaling, and this RET/PTC1 effect can be reversed by
activating cAMP-PKA pathways."
Signaling through 3',5'-cyclic adenosine monophosphate and phosphoinositide-3 kinase induces sodium/iodide symporter expression in breast cancer.Knostman KA, Cho JY, Ryu KY, Lin X, McCubrey JA, Hla T, Liu CH, Di Carlo E, Keri R, Zhang M, Hwang DY, Kisseberth WC, Capen CC, Jhiang SM. J Clin Endocrinol Metab. 2004 Oct;89(10):5196-203.
"The sodium/iodide symporter (NIS) is a membrane transport glycoprotein normally expressed in the thyroid gland and lactating mammary gland. NIS is a target for radioiodide imaging and therapeutic ablation of thyroid carcinomas and has the potential for similar use in breast cancer treatment. To facilitate NIS-mediated radionuclide therapy, it is necessary to identify signaling pathways that lead to increased NIS expression and function in breast cancer. We examined NIS expression in mammary tumors of 14 genetically engineered mouse models to identify genetic manipulations associated with NIS induction. The cAMP and phosphoinositide-3 kinase (PI3K) signaling pathways are associated with NIS up-regulation. We showed that activation of PI3K alone is sufficient to increase NIS expression and radioiodide uptake in MCF-7 human breast cancer cells, whereas cAMP stimulation increases NIS promoter activity and NIS mRNA levels but is not sufficient to increase radioiodide uptake. This study is the first to demonstrate that NIS expression is induced by cAMP and/or PI3K in breast cancer both in vivo and in vitro."
Application of the Cre/loxP system to enhance thyroid-targeted expression of sodium/iodide symporter.Lin X, Fischer AH, Ryu KY, Cho JY, Sferra TJ, Kloos RT, Mazzaferri EL, Jhiang SM. J Clin Endocrinol Metab. 2004 May;89(5):2344-50.
"Radioiodide uptake
activity mediated by the human Na(+)/I(-) symporter (hNIS) in thyroid
follicular cells is the basis for effective (131)I therapy in thyroid
cancer. However, radioiodide therapy is not effective in patients with
thyroid cancer displaying low or absent hNIS expression. This study
assessed the Cre/loxP system for enhancing thyroid-targeted hNIS
expression driven by the thyroglobulin (Tg) promoter. The following
three recombinant adenoviruses (rAd) were constructed: rAd-Tg-hNIS
drives hNIS expression by the Tg promoter; rAd-Tg-Cre drives Cre
expression by the Tg promoter; and rAd-CMV-loxP-hNIS drives hNIS
expression by the cytomegalovirus (CMV) promoter after Cre-mediated
excision of an intervening loxP-GFP-Zeo-loxP. Immortalized normal and
malignant rat thyroid cell lines and primary cultures of normal human
thyroid and human follicular adenoma cells were investigated. We found
that the relative promoter activity of Tg vs. CMV is critical for the
efficacy of the Cre/loxP system. In cells with weak Tg promoter
activity, coinfection of rAd-Tg-Cre and rAd-CMV-loxP-hNIS induced
higher hNIS expression than single infection of rAd-Tg-hNIS. Finally,
Tg promoter activity was partially restored in malignant thyroid cells
by forced expression of the paired domain-containing transcription
factor (Pax-8), allowing the Cre/loxP system to mildly enhance
radioiodide uptake."
Cloning of the 5'-flanking region of mouse sodium/iodide symporter and identification of a thyroid-specific and TSH-responsive enhancer.Lin X, Ryu KY, Jhiang SM. Thyroid. 2004 Jan;14(1):19-27. [abstract only]
" The sodium/iodide symporter (NIS) mediates active iodide uptake into thyroid follicular cells and is important for the diagnosis and radioiodide treatment of thyroid cancers. In order to better investigate the transcriptional regulation of the NIS gene, we cloned the 3.2 kb 5'-flanking region of the mouse NIS (mNIS) gene in this study. The cloned 5'-flanking region of mNIS shares 68% identity with that of rat NIS (rNIS), yet has little similarity to that of human NIS (hNIS). Based on sequence homology to rNIS, the putative mNIS transcriptional start site is mapped to -97 nt relative to the ATG site. The minimal promoter of mNIS is located within 650 bp of the 5'-flanking region as determined by the transient expression analysis of promoter-reporter constructs. The mNIS upstream enhancer (mNUE) was identified based on sequence homology to rNUE. The mNUE is localized to the region between -3042 and -2809 nt relative to the ATG site and shares 94.4% identity with rat NUE (rNUE), while only 67.8% identity with human NUE (hNUE). It contains two Pax-8 binding sites and a Tax/CREB binding site. The mNUE is also demonstrated to confer thyroid-specific and TSH-responsive transcriptional activity. The high degree of homology in the 5'-flanking region between mNIS and rNIS suggests that mNIS and rNIS share similar mechanisms for transcriptional regulation."
Effects of dose, intervention time, and radionuclide on sodium iodide symporter (NIS)-targeted radionuclide therapy.Shen DH, Marsee DK, Schaap J, Yang W, Cho JY, Hinkle G, Nagaraja HN, Kloos RT, Barth RF, Jhiang SM. Gene Ther. 2004 Jan;11(2):161-9. [abstract only] "The sodium iodide symporter (NIS) mediates iodide uptake into thyrocytes and is the molecular basis of thyroid radioiodine therapy. We previously have shown that NIS gene transfer into the F98 rat gliomas facilitated tumor imaging and increased survival by radioiodine. In this study, we show that: (1) the therapeutic effectiveness of (131)I in prolonging the survival time of rats bearing F98/hNIS gliomas is dose- and treatment-time-dependent; (2) the number of remaining NIS-expressing tumor cells decreased greatly in RG2/hNIS gliomas post (131)I treatment and was inversely related to survival time; (3) 8 mCi each of (125)I/(131)I is as effective as 16 mCi (131)I alone, despite a smaller tumor absorbed dose; (4) (188)ReO(4), a potent beta(-) emitter, is more efficient than (131)I to enhance the survival of rats bearing F98/hNIS gliomas. These studies demonstrate the importance of radiopharmaceutical selection, dose, and timing of treatment to optimize the therapeutic effectiveness of NIS-targeted radionuclide therapy following gene transfer into gliomas."
Effect of exogenous human sodium iodide symporter expression on growth of MATLyLu cells.La Perle KM, Blomme EA, Capen CC, Jhiang SM. Thyroid. 2003 Feb;13(2):133-40. [abstract only]
"The sodium iodide
symporter (NIS) mediates iodide uptake in thyroid cells and enables
the effective radioiodide treatment of thyroid cancers. There is much
interest in facilitating radioiodide therapy in other cancers by NIS
gene transfer. This study showed that exogenous NIS expression
decreased MATLyLu rat prostatic adenocarcinoma cell growth. Tumor
growth and metastatic progression were significantly delayed in
syngeneic rats injected with mixed or clonal populations of MATLyLu-NIS
cells compared to rats with control tumors. MATLyLu-NIS tumors in nude
mice had a lower, albeit not statistically significant, growth rate
than control tumors. The Ki-67 labeling index in NIS-positive areas
was lower than in NIS-negative areas of rat tumors derived from a
mixed population of MATLyLu-NIS cells. Growth of clonal populations of
MATLyLu-NIS cells was delayed in vitro. These results demonstrate that
NIS expression inhibits MATLyLu cell growth, thereby providing an
additional potential benefit of NIS-mediated gene therapy for cancer."
In vivo imaging and radioiodine therapy following sodium iodide symporter gene transfer in animal model of intracerebral gliomas.Cho JY, Shen DH, Yang W, Williams B, Buckwalter TL, La Perle KM, Hinkle G, Pozderac R, Kloos R, Nagaraja HN, Barth RF, Jhiang SM. Gene Ther. 2002 Sep;9(17):1139-45.
"Radioactive iodide uptake (RAIU) in thyroid follicular epithelial cells, mediated by the sodium iodide symporter (NIS), is the first rate-limiting step in iodide accumulation which provides a mechanism for effective radioiodide treatment for patients with thyroid cancer. We hypothesize that NIS gene transfer to non-thyroid tumor cells will enhance intracellular radioiodide accumulation and result in better tumor control. Here, we performed non-invasive tumor imaging and (131)I therapy studies using rats bearing intracerebral F98 gliomas that have been retrovirally transduced with human NIS. Our results show that: (1) NIS is expressed in the intracerebral F98/NIS gliomas; (2) F98/NIS gliomas can be imaged by (99m)TcO(4) (whose uptake is also mediated by NIS) and (123)I scintigraphy; (3) significant amounts of radioiodide were retained in the tumors at 24 h after (123)I injection; (4) RAIU and NIS expression in the thyroid gland can be reduced by feeding a thyroxine-supplemented diet; and (5) survival time was increased in rats bearing F98/hNIS tumors by (131)I treatment. These studies warrant further investigating tumor imaging and therapeutic strategies based on NIS gene transfer followed by radioiodide administration in a variety of human cancers."
In vivo expression and function of the sodium iodide symporter following gene transfer in the MATLyLu rat model of metastatic prostate cancer.La Perle KM, Shen D, Buckwalter TL, Williams B, Haynam A, Hinkle G, Pozderac R, Capen CC, Jhiang SM. Prostate. 2002 Feb 15;50(3):170-8. [abstract only]
"BACKGROUND: The sodium iodide symporter (NIS) mediates iodide uptake in thyroid follicular cells and provides a mechanism for effective radioiodide treatment of residual, recurrent, and metastatic thyroid cancers. This study investigated the clinical applications of NIS gene transfer for prostate cancer using the MATLyLu metastatic rat model.
METHODS: MATLyLu cells expressing NIS were injected subcutaneously in Copenhagen rats, which developed metastases in lymph nodes and lungs. NIS protein expression was evaluated by Western blot and immunohistochemistry, and function was measured by tissue gamma counts and whole-body imaging following radionuclide administration.
RESULTS: In vitro radioiodide-concentrating activity was increased up to 72-fold in a mixed population of MATLyLu-hNIS cells. NIS protein expression was confirmed in subcutaneous MATLyLu-hNIS tumors by immunohistochemistry and Western blot. Gamma counts of subcutaneous MATLyLu-hNIS tumors were 23-fold higher than parental MATLyLu tumors and radionuclide uptake in subcutaneous MATLyLu-hNIS tumors and lymph node metastases was visualized by whole-body image analysis.
CONCLUSIONS: NIS expression by a proportion of cells in a population was sufficient to confer radionuclide-concentrating function in subcutaneous and metastatic MATLyLu tumors. Ablation of residual normal and neoplastic prostate tissues by radioiodide after prostate-restricted NIS gene transfer might be a novel adjuvant therapy to prostatectomy for the treatment of advanced prostate cancer."
Sodium iodide symporter in health and disease.Shen DH, Kloos RT, Mazzaferri EL, Jhiang SM. Thyroid. 2001 May;11(5):415-25. Review.
"Radioiodine-concentrating activity in thyroid tissues has allowed the use of radioiodine as a diagnostic and therapeutic agent for patients with thyroid disorders such as well-differentiated thyroid cancer. However, some extrathyroidal tissues also take up radioiodine, contributing to unwanted side effects of radioiodine therapy. Now that the molecule that mediates radioiodine uptake, the sodium iodide symporter (NIS), has been cloned and characterized, it may be possible to develop novel strategies to differentially modulate NIS expression and/or activity, enhancing it in target tissues and impeding it in others. In addition to restoring NIS expression/activity to ensure sufficient radioiodine uptake for the diagnosis and treatment of advanced thyroid cancers, we envision that it may be possible to selectively increase or confer NIS expression/activity in tumors of nonthyroidal tissues to facilitate the use of radioiodine in their diagnosis and treatment. We also consider the molecular basis of thyroid and nonthyroid disorders that may be complicated by NIS deregulation. Finally, we explore the use of NIS as an imaging reporter gene to monitor the expression profile of the transgene in transgenic mouse animal models and in patients undergoing gene therapy clinical trials."
Regulation of sodium/iodide symporter.Jhiang SM. Rev Endocr Metab Disord. 2000 Apr;1(3):205-15. Review. [citation only]
Monoclonal antibodies against the human sodium iodide symporter: utility for immunocytochemistry of thyroid cancer.Castro MR, Bergert ER, Beito TG, Roche PC, Ziesmer SC, Jhiang SM, Goellner JR, Morris JC. J Endocrinol.
1999 Dec;163(3):495-504. "The recent cloning of the thyroidal protein that is responsible for iodide transport, the sodium iodide symporter (hNIS), has made possible studies designed to characterize its structure, function and expression in thyroidal tissues. Using a mannose binding protein (MBP)-hNIS fusion protein as antigen, we have developed mouse monoclonal antibodies against hNIS to utilize as tools in such studies. Twenty-four clones were initially recovered which recognized the MBP-hNIS fusion protein, but only two of them were specific for hNIS while the others recognized MBP alone. Both antibodies were found to be immunoglobulin G (IgG) 1kappa (kappa). The specificity of antibodies was tested by Western blotting using membranes prepared from COS-7 cells transiently transfected with the pcDNA3 plasmid containing the full-length hNIS cDNA, or cells transfected with the pcDNA3 vector. A major band with a molecular weight (MW) of approximately 97 kDa, and several minor bands with MW of approximately 160 kDa, approximately 68 kDa, approximately 30 kDa and approximately 15 kDa, were detected specifically in the hNIS-transfected cells. After enzymatic deglycosylation, the major band was present at 68 kDa, as expected based upon the amino acid sequence of hNIS. Immunohistochemistry was performed with several different types of thyroid tissue and non-thyroidal tissues, using the monoclonal antibodies. Strong immunostaining was observed in Graves' tissue, with intermediate staining in papillary and follicular thyroid cancers and an absence of staining in Hurthle cell cancer. The staining was specific for the follicular epithelium and was concentrated in the basolateral portion of the cell membrane. These monoclonal hNIS antibodies should prove useful in the characterization of NIS expression in benign and malignant thyroid tissue and in studies characterizing its structure and function."
Development of monoclonal antibodies against the human sodium iodide symporter: immunohistochemical characterization of this protein in thyroid cells.Castro MR, Bergert ER, Beito TG, McIver B, Goellner JR, Morris JC. J Clin Endocrinol Metab. 1999 Aug;84(8):2957-62.
"The thyroid sodium-iodide symporter (NIS) is responsible for iodide concentrating ability within thyroid follicular cells. We sought to develop monoclonal antibodies against human NIS (hNIS) for use as reagents in structure-function studies of the protein, as well as potential tools in the assessment of NIS expression in benign and malignant thyroid tissues. Synthetic peptides corresponding to the second ExMD and to the carboxy-terminal ExMD of hNIS were produced and utilized as antigens to develop monoclonal antibodies, which were tested by Western blotting using membranes prepared from COS-7 cells transiently transfected with a pcDNA3 plasmid containing the gene for the full-length hNIS, or a control vector. Western blotting showed a major band with molecular weight (MW) of approximately 97 kDa and several minor bands with MW of approximately 160 kDa, 68 kDa, 30 kDa, and 15 kDa, all specific for hNIS-transfected cells. Immunohistochemistry was performed in various types of thyroid tissues and nonthyroidal tissues, using the monoclonal antibodies. Strong immunostaining was observed in Graves' tissue, intermediate staining in papillary and follicular thyroid cancer, and no staining in Hurthle cell cancer or in nonthyroidal tissue. The staining was specific for the follicular epithelium in each of the tissues and was most intense in the basolateral portion of the cell membrane. Overall, our observations indicate that the monoclonal antibodies are specific for hNIS and will be invaluable reagents for investigating the role of NIS in thyroid disease."
An immunohistochemical study of Na+/I- symporter in human thyroid tissues and salivary gland tissues.Jhiang SM, Cho JY, Ryu KY, DeYoung BR, Smanik PA, McGaughy VR, Fischer AH, Mazzaferri EL. Endocrinology. 1998 Oct;139(10):4416-9.
"The human Na+/I- symporter (hNIS) is the plasma membrane protein that mediates active iodide uptake into several tissues, such as the thyroid and salivary glands. To study the distribution and cellular localization of the hNIS protein, we have generated a polyclonal antibody that could detect the hNIS protein by immunohistochemical staining on tissue sections. In normal thyroids, hNIS expression is heterogeneous, and it is only detected in sporadic thyrocytes of a given follicle. The hNIS protein was not detected in thyroid carcinomas, yet it was detected in the majority of thyrocytes in Graves' thyroids. In salivary glands, hNIS protein was not detected in acinar cells, but it was detected in ductal cells. The hNIS proteins are clustered in the basal and lateral membranes in cells stained positive for hNIS."
Expression, exon-intron organization, and chromosome mapping of the human sodium iodide symporter.Smanik PA, Ryu KY, Theil KS, Mazzaferri EL, Jhiang SM. Endocrinology. 1997 Aug;138(8):3555-8.
"The active iodide uptake of the thyroid gland in humans is mediated by the human sodium iodide symporter (hNIS). In this report, we show that hNIS expression was detected primarily in thyroid tissue, but also in breast, colon, and ovary tissues. Expression of hNIS is greatly reduced in thyroid tumors compared to normal thyroid tissue. Among tumor tissues, hNIS expression appears to be variable, consistent with the variable response to radioiodide treatment observed for thyroid carcinomas. The coding region of hNIS is interrupted by 14 introns, and the nucleotide sequence of each exon-intron junction is reported. Using this information, an alternatively spliced form of hNIS was identified. Finally, the chromosome location of the hNIS gene was mapped to chromosome 19p."
Cloning of the human sodium lodide symporter.Smanik PA, Liu Q, Furminger TL, Ryu K, Xing S, Mazzaferri EL, Jhiang SM. Biochem Biophys Res Commun. 1996 Sep 13;226(2):339-45. [abstract only]
"The iodide concentrating activity of the thyroid gland is essential to the production of thyroid hormone and also provides a mechanism for the treatment of thyroid cancer by radioiodine ablation. We report here the nucleotide and amino acid sequence of the human sodium iodide symporter (hNIS), which mediates the iodide uptake activity in the thyroid gland. An open reading frame of 1929 nucleotides encodes a protein of 643 amino acids with 84% identity to the rat NIS (rNIS). Transient expression of the hNIS cDNA conferred perchlorate-sensitive iodide uptake to a nonthyroid cell line, COS-7. The expression of hNIS was detected at variable levels in papillary thyroid carcinoma tissues but not in any of the thyroid carcinoma cell lines that have lost the iodide uptake activity."
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