Abstract
Forkhead box P3 (FoxP3) expression in papillary thyroid carcinoma (PTC) is associated with resistance to radioiodine treatment. The sodium iodine symporter (NIS) is a plasma membrane glycoprotein, the repression of which may render the tumor refractive to radioiodine therapy. In this study, samples from 90 PTCs as well as 40 normal thyroid tissues were examined for FoxP3 and NIS by immunohistochemistry and real-time PCR. We found that FoxP3 was associated with decreased NIS expression. Lentiviral-mediated FoxP3-overexpressing cells were constructed and real-time PCR and western blotting were performed to evaluate the expression of NIS. Meanwhile, key members of the transforming growth factor-β1 (TGF-β1) pathway were explored by ELISA and immunofluorescence and a neutralizing TGF-β1 antibody was used to block activity. In vitro, FoxP3 overexpression significantly reduced NIS transcript and protein levels and the TGF-β1 pathway was activated. However, treatment with neutralizing TGF-β1 antibody partially abrogated FoxP3-induced NIS repression. These findings suggest that FoxP3 could compromise NIS expression by inducing TGF-β1.
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References
Xing MZ. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer. 2013;13:184–99.
Lopes JP, Fonseca E. BRAF gene mutation in the natural history of papillary thyroid carcinoma: diagnostic and prognostic implications. Acta Med Port. 2011;4:855–68.
Lakshmanan A, Scarberry D, Shen DH, Jhiang SM. Mutation of sodium iodine symporter in thyroid cancer. Horm Cancer. 2014;5:363–73.
Chung JK, Cheon GJ. Radioiodine therapy in differentiated thyroid cancer: the first targeted therapy in oncology. Endocrinol Metab. 2014;29:233–9.
Kogai T, Brent GA. The sodium iodide symporter (NIS): regulation and approaches to targeting for cancer therapeutics. Pharmacol Ther. 2014;135:355–70.
Mincione G, Di Marcantonio MC, Tarantelli C, D’Inzeo S, Nicolussi A, Nardi F, Donini CF, Coppa A. EGF and TGF-β1 effects on thyroid function. J Thyroid Res. 2011; 431718.
Serrano-Nascimento C, da Silva Teixeira S, Nicola JP, Nachbar RT, Masini-Repiso AM, Nunes MT. The acute inhibitory effect of iodide excess on sodium/iodide symporter expression and activity involves the PI3K/Akt signaling pathway. Endocrinology. 2014;155:1145–56.
Xu S, Chen G, Peng W, Renko K, Derwahl M. Oestrogen action on thyroid progenitor cells: relevant for the pathogenesis of thyroid nodules? J Endocrinol. 2013;218:125–33.
Costamagna E, Garıa B, Santisteban P. The functional interaction between the paired domain transcription factor Pax8 and Smad3 is involved in transforming growth factor-beta repression of the sodium/iodide symporter gene. Biol Chem. 2004;5:3439–46.
Eloy C, Santos J, Cameselle-Teijeiro J, Soares P, Sobrinho-Simões M. TGF-beta/Smad pathway and BRAF mutation play different roles in circumscribed and infiltrative papillary thyroid carcinoma. Virchows Arch. 2012;460:587–600.
Zhang J, Wang Y, Li D, Jing S. Notch and TGF-β1/Smad3 pathways are involved in the interaction between cancer cells and cancer-associated fibroblasts in papillary thyroid. Tumour Biol. 2014;35:379–85.
Poveda KT, Román MB, González C, García AB, Morales VHB, Zaragoza OP, et al. Role of IL-10 and TGF-β1 in local immunosuppression in HPV associated cervical neoplasia. World J Clin Oncol. 2014;5:753–63.
D'Inzeo S, Nicolussi A, Donini CF, Zani M, Mancini P, Nardi F, et al. A novel human Smad4 mutation is involved in papillary thyroid carcinoma. Endocr Relat Cancer. 2012;19:39–55.
Brown KA, Pietenpol JA, Moses HL. A tale of two proteins: differential roles and regulation of Smad2 and Smad3 in TGF-β signaling. J Cell Biochem. 2007;101:9–33.
Hori S. Stability of regulatory T-cell lineage. Adv Immunol. 2011;112:1–24.
Haque R, Lei F, Xiong X, Song J. The regulation of FoxP3-expressing regulatory T cells. Endocr Metab Immune Disord Drug Targets. 2011;11:334–46.
Ebert LM, Tan BS, Browning J, Svobodova S, Russell SE, Kirkpatrick N, et al. The regulatory T cell-associated transcription factor FoxP3 is expressed by tumor cells. Cancer Res. 2008;68:3001–9.
Ma GF, Chen SY, Sun ZR, Miao Q, Liu YM, Zeng XQ, et al. FoxP3 inhibits proliferation and induces apoptosis of gastric cancer cells by activating the apoptotic signaling pathway. Biochem Biophys Res Commun. 2013;430:804–9.
Chu R, Vlantis AC, van Hasselt CA, Ng SK. Inhibition of FoxP3 induced apoptosis of thyroid cancer cells. Mol Cell Endocrinol. 2015;399:228–34.
Liang YJ, Liu HC, Su YX, Zhang TH, Chu M, Liang LZ, et al. FoxP3 expressed by tongue squamous cell carcinoma cells correlates with clinicopathologic features and overall survival in tongue squamous cell carcinoma patients. Oral Oncol. 2011;47:566–70.
Hinz S, Pagerols-Raluy L, Oberg HH, Ammerpohl O, Grussel S, Sipos B, et al. FoxP3 expression in pancreatic carcinoma cells as a novel mechanism of immune evasion in cancer. Cancer Res. 2007;67:8344–50.
Niu J, Jiang C, Li C, Liu L, Li K, Jian Z, et al. Foxp3 expression in melanoma cells as a possible mechanism of resistance to immune destruction. Cancer Immunol Immunother. 2011;60:1109–18.
Liang YJ, Lao XM, Liang LZ. Genome-wide analysis of cancer cell-derived FoxP3 target genes in human tongue squamous cell carcinoma cells. Int J Oncol. 2015;46:1935–43.
Schipmann S, Wermker K, Schulze HJ, Kleinheinz J, Brunner G. Cutaneous and oral squamous cell carcinoma-dual immunosuppression via recruitment of FoxP3(+) regulatory T cells and endogenous tumour FoxP3 expression? J Craniomaxillofac Surg. 2014;42:1827–33.
Clara U, Rossella E, Agnese P, Serena P, Cristiana L, Nicla B, et al. FoxP3 expression in papillary thyroid carcinoma: a possible resistance biomarker to iodine 131 treatment. Thyroid. 2014;24:339–46.
Dohan O, De La Vieja A, Paroder V, Riedel C, Artani M, Reed M, et al. Endocr Rev. 2003;24:48–77.
Liu F, Ma XJ, Zhao YY, Wu LN, Zhao YY, Qin GJ. The effect of FoxO1 on the proliferation of rat mesangial cells under high glucose conditions. DNT. 2014;29:1879–87.
Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T). Nat Protoc. 2008;3:1101–8.
Riesco-Eizaguirre G, Rodríguez I, De la Vieja A, Costamagna E, Carrasco N, Nistal M, et al. The BRAFV600E oncogene induces transforming growth factor β secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. Cancer Res. 2009;69:8317–25.
David A, Daniel B, Michael J, Toni B, Alexander J, Veach P, et al. Thyroid stimulating hormone increases iodine uptake by thyroid cancer cells during BRAF silencing. J Surg Res. 2013;182:85–93.
Morari EC, Marcello MA, Guilhen AC, Cunha LL, Latuff P, Soares FA, et al. Use of sodium iodine symporter expression in differentiated thyroid carcinomas. Clin Endocrinol. 2011;75:247–54.
Acknowledgments
This work was supported by grants from the Innovation Scientists and Technicians Troop Construction Projects of Henan Province (No. 134200510021). The authors appreciate the generous help of the Institute of Clinical Medicine (The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) in providing the necessary facilities, and Jun Ouyang and Jinfa Li from the endocrinology laboratory of The First Affiliated Hospital of Zhengzhou University.
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Ma, S., Wang, Q., Ma, X. et al. FoxP3 in papillary thyroid carcinoma induces NIS repression through activation of the TGF-β1/Smad signaling pathway. Tumor Biol. 37, 989–998 (2016). https://doi.org/10.1007/s13277-015-3848-6
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DOI: https://doi.org/10.1007/s13277-015-3848-6