The expression of FoxP3 in papillary thyroid carcinoma and its relationship with the therapeutic dose of <sup>131</sup>I_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

YANG Huifang ^1,2 , CHEN Song ^2,3 , GAO Qingjun ¹ ,  ZHAO Daiwei ¹

1. Department of Thyroid Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, P. R. China;
2. Clinical Medicine College of Guizhou Medical University, Guiyang 550004, P. R. China;
3. Department of Thyroid and Breast Surgery, Jinyang Hospital Affiliated to Guizhou Medical University, Guiyang 550081, P. R. China;

Corresponding author：

ZHAO Daiwei, Email: zhaodw@hotmail.com

Keywords：

forkhead box P3; papillary thyroid carcinoma; nodular goiter; immunohistochemistry; ¹³¹I therapeutic dose

DOI：

10.7507/1007-9424.202106107

Video：

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Objective To analyze the expression differences of FoxP3 protein in papillary thyroid carcinoma (PTC) and nodular goiter, and to explore the correlation between FoxP3 and the clinicopathological characteristics of PTC patients and the therapeutic dose of ¹³¹I. Methods Immunohistochemical method was used to detect the expression of FoxP3 protein in 128 cases of PTC tissues (42 cases were treated with ¹³¹I after operation) and 20 cases of nodular thyroid tissues, and the relationship between it and the clinicopathological characteristics of PTC patients and the dose of ¹³¹I treatment was also analyzed. Results The positive rate of FoxP3 protein expression in PTC tissues was 46.09%, which was higher than that in nodular goiter tissues (0.00%), and the difference was statistically significant (P<0.001). The expression of FoxP3 protein in PTC was correlated with gender, extraglandular invasion and tumor diameter (P values were 0.041, 0.039, and 0.007, respectively), but had no correlation with age, capsular invasion, TNM staging, lymph node metastasis, and distant metastasis (P>0.05). The results of binary logistic regression analysis suggest that tumor diameter was an independent risk factor affecting FoxP3 protein expression [OR=0.389, 95%CI (0.180, 0.840), P=0.016]. By drawing the receiver operating characteristic (ROC) curve, it was shown that the area under the curve (AUC) was 0.643 when the tumor diameter was 1.05 cm, the sensitivity to predict the increase in FoxP3 protein expression was 64.41%, and the specificity was 57.97%, P=0.006. Among 42 patients with PTC who underwent ¹³¹I treatment after surgery, the therapeutic dose of ¹³¹I was related to the expression of FOXP3 protein (P=0.031). It was shown that patients with positive expression of FoxP3 protein were given more dose of ¹³¹I after surgery. Conclusions The positive rate of FoxP3 protein expression in PTC is higher than that of nodular goiter. Its high expression means that the patient has poor pathological characteristics and larger ¹³¹I treatment dose, suggesting that FoxP3 may be involved in the malignant progression of PTC.

Citation： YANG Huifang, CHEN Song, GAO Qingjun, ZHAO Daiwei. The expression of FoxP3 in papillary thyroid carcinoma and its relationship with the therapeutic dose of ¹³¹I. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2021, 28(12): 1575-1579. doi: 10.7507/1007-9424.202106107 Copy

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2.	Zheng H, Wang M, Jiang L, et al. BRAF-activated long noncoding RNA modulates papillary thyroid carcinoma cell proliferation through regulating thyroid stimulating hormone receptor. Cancer Res Treat, 2016, 48(2): 698-707.
3.	Gong L, Chen P, Liu X, et al. Expressions of D2-40, CK19, galectin-3, VEGF and EGFR in papillary thyroid carcinoma. Gland Surg, 2012, 1(1): 25-32.
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5.	Goto R, Hirota Y, Aruga T, et al. The number of FoxP3-positive tumor-infiltrating lymphocytes in patients with synchronous bilateral breast cancer. Breast Cancer, 2020, 27(4): 586-593.
6.	Ma K, Li X, Lv J, et al. Correlations between CD4⁺ FoxP3⁺ Treg and expression of FoxM1 and Ki-67 in gastric cancer patients. Asia Pac J Clin Oncol, 2021, 17(2): e63-e69.
7.	Wang R, Huang K. CCL11 increases the proportion of CD4⁺CD25⁺Foxp3⁺ Treg cells and the production of IL-2 and TGF-β by CD4⁺ T cells via the STAT5 signaling pathway. Mol Med Rep, 2020, 21(6): 2522-2532.
8.	Wang X, Lang M, Zhao T, et al. Cancer-FOXP3 directly activated CCL5 to recruit FOXP3⁺ Treg cells in pancreatic ductal adenocarcinoma. Oncogene, 2017, 36(21): 3048-3058.
9.	Zhang H, Zhang S. The expression of Foxp3 and TLR4 in cervical cancer: association with immune escape and clinical pathology. Arch Gynecol Obstet, 2017, 295(3): 705-712.
10.	Gao S, Wang Y, Wang M, et al. MicroRNA-155, induced by FOXP3 through transcriptional repression of BRCA1, is associated with tumor initiation in human breast cancer. Oncotarget, 2017, 8(25): 41451-41464.
11.	Li F, Sun Y, Huang J, et al. CD4/CD8⁺ T cells, DC subsets, Foxp3, and IDO expression are predictive indictors of gastric cancer prognosis. Cancer Med, 2019, 8(17): 7330-7344.
12.	Chen Y, Qi X, Bian C, et al. The association of FOXP3 gene polymorphisms with cancer susceptibility: a comprehensive systemic review and meta-analysis. Biosci Rep, 2019, 39(3): BSR20181809.
13.	杨晓燕, 郭永, 贾睿博, 等. FoxP3在甲状腺乳头状癌中的表达及与预后的相关性. 安徽医学, 2017, 38(4): 456-459.
14.	Amin MB, Edge S, Greene F, et al. 2017 AJCC Cancer Staging Manual. Eighth ed. New York: Springer, 2017: 55-67.
15.	Rotte A, Bhandaru M, Cheng Y, et al. Decreased expression of nuclear p300 is associated with disease progression and worse prognosis of melanoma patients. PLoS One, 2013, 8(9): e75405.
16.	中华医学会内分泌学分会, 中华医学会外科学分会, 中国抗癌协会头颈肿瘤专业委员会, 等. 甲状腺结节和分化型甲状腺癌诊治指南. 中国肿瘤临床, 2012, 39(17): 1249-1272.
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18.	Ahmadi S, Gonzalez JM, Talbott M, et al. Patient preferences around extent of surgery in low-risk thyroid cancer: a discrete choice experiment. Thyroid, 2020, 30(7): 1044-1052.
19.	Coca-Pelaz A, Shah JP, Hernandez-Prera JC, et al. Papillary thyroid cancer-aggressive variants and impact on management: a narrative review. Adv Ther, 2020, 37(7): 3112-3128.
20.	Rahman ST, McLeod DSA, Pandeya N, et al. Understanding pathways to the diagnosis of thyroid cancer: are there ways we can reduce over-diagnosis? Thyroid, 2019, 29(3): 341-348.
21.	Cavalleri T, Bianchi P, Basso G, et al. Combined low densities of FoxP3⁺ and CD3⁺ tumor-infiltrating lymphocytes identify stage Ⅱ colorectal cancer at high risk of progression. Cancer Immunol Res, 2019, 7(5): 751-758.
22.	Ohue Y, Nishikawa H. Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target? Cancer Sci, 2019, 110(7): 2080-2089.
23.	Mohamed SY, Ibrahim TR, Elbasateeny SS, et al. Clinico-pathological characterization and prognostic implication of FOXP3 and CK19 expression in papillary thyroid carcinoma and concomitant Hashimoto's thyroiditis. Sci Rep, 2020, 10(1): 10651.
24.	赵水英, 秦贵军, 李志臻, 等. 甲状腺乳头状癌组织中Foxp3的表达. 郑州大学学报(医学版), 2021, 56(2): 246-249.
25.	Chu R, Liu SY, Vlantis AC, et al. Inhibition of Foxp3 in cancer cells induces apoptosis of thyroid cancer cells. Mol Cell Endocrinol, 2015, 399: 228-234.
26.	Jaber T, Waguespack SG, Cabanillas ME, et al. Targeted therapy in advanced thyroid cancer to resensitize tumors to radioactive iodine. J Clin Endocrinol Metab, 2018, 103(10): 3698-3705.
27.	Rothenberg SM, McFadden DG, Palmer EL, et al. Redifferentiation of iodine-refractory BRAF V600E-mutant metastatic papillary thyroid cancer with dabrafenib. Clin Cancer Res, 2015, 21(5): 1028-1035.
28.	Taïeb D, Jacob T, Zotian E, et al. Lack of efficacy of recombinant human thyrotropin versus thyroid hormone withdrawal for radioiodine therapy imaging in a patient with differentiated thyroid carcinoma lung metastases. Thyroid, 2004, 14(6): 465-467.
29.	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. Tumour Biol, 2016, 37(1): 989-998.

1. Kitahara CM, Sosa JA. The changing incidence of thyroid cancer. Nat Rev Endocrinol, 2016, 12(11): 646-653.
2. Zheng H, Wang M, Jiang L, et al. BRAF-activated long noncoding RNA modulates papillary thyroid carcinoma cell proliferation through regulating thyroid stimulating hormone receptor. Cancer Res Treat, 2016, 48(2): 698-707.
3. Gong L, Chen P, Liu X, et al. Expressions of D2-40, CK19, galectin-3, VEGF and EGFR in papillary thyroid carcinoma. Gland Surg, 2012, 1(1): 25-32.
4. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association Management Guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid, 2016, 26(1): 1-133.
5. Goto R, Hirota Y, Aruga T, et al. The number of FoxP3-positive tumor-infiltrating lymphocytes in patients with synchronous bilateral breast cancer. Breast Cancer, 2020, 27(4): 586-593.
6. Ma K, Li X, Lv J, et al. Correlations between CD4⁺ FoxP3⁺ Treg and expression of FoxM1 and Ki-67 in gastric cancer patients. Asia Pac J Clin Oncol, 2021, 17(2): e63-e69.
7. Wang R, Huang K. CCL11 increases the proportion of CD4⁺CD25⁺Foxp3⁺ Treg cells and the production of IL-2 and TGF-β by CD4⁺ T cells via the STAT5 signaling pathway. Mol Med Rep, 2020, 21(6): 2522-2532.
8. Wang X, Lang M, Zhao T, et al. Cancer-FOXP3 directly activated CCL5 to recruit FOXP3⁺ Treg cells in pancreatic ductal adenocarcinoma. Oncogene, 2017, 36(21): 3048-3058.
9. Zhang H, Zhang S. The expression of Foxp3 and TLR4 in cervical cancer: association with immune escape and clinical pathology. Arch Gynecol Obstet, 2017, 295(3): 705-712.
10. Gao S, Wang Y, Wang M, et al. MicroRNA-155, induced by FOXP3 through transcriptional repression of BRCA1, is associated with tumor initiation in human breast cancer. Oncotarget, 2017, 8(25): 41451-41464.
11. Li F, Sun Y, Huang J, et al. CD4/CD8⁺ T cells, DC subsets, Foxp3, and IDO expression are predictive indictors of gastric cancer prognosis. Cancer Med, 2019, 8(17): 7330-7344.
12. Chen Y, Qi X, Bian C, et al. The association of FOXP3 gene polymorphisms with cancer susceptibility: a comprehensive systemic review and meta-analysis. Biosci Rep, 2019, 39(3): BSR20181809.
13. 杨晓燕, 郭永, 贾睿博, 等. FoxP3在甲状腺乳头状癌中的表达及与预后的相关性. 安徽医学, 2017, 38(4): 456-459.
14. Amin MB, Edge S, Greene F, et al. 2017 AJCC Cancer Staging Manual. Eighth ed. New York: Springer, 2017: 55-67.
15. Rotte A, Bhandaru M, Cheng Y, et al. Decreased expression of nuclear p300 is associated with disease progression and worse prognosis of melanoma patients. PLoS One, 2013, 8(9): e75405.
16. 中华医学会内分泌学分会, 中华医学会外科学分会, 中国抗癌协会头颈肿瘤专业委员会, 等. 甲状腺结节和分化型甲状腺癌诊治指南. 中国肿瘤临床, 2012, 39(17): 1249-1272.
17. Schmidt Jensen J, Grønhøj C, Mirian C, et al. Incidence and survival of thyroid cancer in children, adolescents, and young adults in denmark: a nationwide study from 1980 to 2014. Thyroid, 2018, 28(9): 1128-1133.
18. Ahmadi S, Gonzalez JM, Talbott M, et al. Patient preferences around extent of surgery in low-risk thyroid cancer: a discrete choice experiment. Thyroid, 2020, 30(7): 1044-1052.
19. Coca-Pelaz A, Shah JP, Hernandez-Prera JC, et al. Papillary thyroid cancer-aggressive variants and impact on management: a narrative review. Adv Ther, 2020, 37(7): 3112-3128.
20. Rahman ST, McLeod DSA, Pandeya N, et al. Understanding pathways to the diagnosis of thyroid cancer: are there ways we can reduce over-diagnosis? Thyroid, 2019, 29(3): 341-348.
21. Cavalleri T, Bianchi P, Basso G, et al. Combined low densities of FoxP3⁺ and CD3⁺ tumor-infiltrating lymphocytes identify stage Ⅱ colorectal cancer at high risk of progression. Cancer Immunol Res, 2019, 7(5): 751-758.
22. Ohue Y, Nishikawa H. Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target? Cancer Sci, 2019, 110(7): 2080-2089.
23. Mohamed SY, Ibrahim TR, Elbasateeny SS, et al. Clinico-pathological characterization and prognostic implication of FOXP3 and CK19 expression in papillary thyroid carcinoma and concomitant Hashimoto's thyroiditis. Sci Rep, 2020, 10(1): 10651.
24. 赵水英, 秦贵军, 李志臻, 等. 甲状腺乳头状癌组织中Foxp3的表达. 郑州大学学报(医学版), 2021, 56(2): 246-249.
25. Chu R, Liu SY, Vlantis AC, et al. Inhibition of Foxp3 in cancer cells induces apoptosis of thyroid cancer cells. Mol Cell Endocrinol, 2015, 399: 228-234.
26. Jaber T, Waguespack SG, Cabanillas ME, et al. Targeted therapy in advanced thyroid cancer to resensitize tumors to radioactive iodine. J Clin Endocrinol Metab, 2018, 103(10): 3698-3705.
27. Rothenberg SM, McFadden DG, Palmer EL, et al. Redifferentiation of iodine-refractory BRAF V600E-mutant metastatic papillary thyroid cancer with dabrafenib. Clin Cancer Res, 2015, 21(5): 1028-1035.
28. Taïeb D, Jacob T, Zotian E, et al. Lack of efficacy of recombinant human thyrotropin versus thyroid hormone withdrawal for radioiodine therapy imaging in a patient with differentiated thyroid carcinoma lung metastases. Thyroid, 2004, 14(6): 465-467.
29. 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. Tumour Biol, 2016, 37(1): 989-998.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

The expression of FoxP3 in papillary thyroid carcinoma and its relationship with the therapeutic dose of ¹³¹I

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The expression of FoxP3 in papillary thyroid carcinoma and its relationship with the therapeutic dose of 131I

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The expression of FoxP3 in papillary thyroid carcinoma and its relationship with the therapeutic dose of ¹³¹I