Correlation between the expressions of BMP4, Smad4 and clinicopathological features in papillary thyroid carcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

 WANG Zongyue ¹ , ZHANG Wanyue ² , MENG FanJie ¹ , GE Wanling ¹ , LIU Chuanliang ¹ , YUAN Qingling ³

1. Second Department of General Surgery, Pingdingshan Second People’s Hospital, Pingdingshan, Henan 467000, P. R. China;
2. Operating Room, Pingdingshan Second People’s Hospital, Pingdingshan, Henan 467000, P. R. China;
3. Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China;

Corresponding author：

WANG Zongyue, Email: ww_1648@163.com

Keywords：

papillary thyroid carcinoma; bone morphogenetic protein 4; sma and mad homologue 4

DOI：

10.7507/1007-9424.202104025

Video：

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Objective To investigate the correlation between the expressions of bone morphogenetic protein 4 (BMP4) and sma and mad homologue 4 (Smad4) and their clinicopathological features in papillary thyroid carcinoma (PTC).Methods Eighty patients with PTC confirmed by pathology in the Pingdingshan Second People’s Hospital from March 2018 to March 2020 were selected as the research objects, the cancer tissues and adjacent tissues removed during surgery were collected. The mRNA expression levels of BMP4 and Smad4 were detected by real-time quantitative PCR (qRT-PCR). The correlation between BMP4 and Smad4 mRNA expression levels was analyzed by Pearson method. The expressions of BMP4 and Smad4 protein were detected by immunohistochemistry. The correlation between the expressions of BMP4 and Smad4 protein and clinicopathological features of PTC was analyzed.Results The mRNA expression levels of BMP4 and Smad4 in PTC tissues were lower than those in adjacent tissues (P<0.05). Pearson analysis showed that there was a positive correlation between expressions of BMP4 mRNA and Smad4 mRNA in PTC cancer (r=0.660, P<0.05). BMP4 and Smad4 protein were localized in cytoplasm, and the cytoplasm was stained yellow or brown yellow. The results of immunohistochemistry showed that the expression positive rate of BMP4 in cancer tissues of PTC patients was lower than that in adjacent tissues (18.8% vs 97.5%, χ²=101.916, P<0.05), and the expression positive rate of Smad4 protein in cancer tissues of PTC patients was also lower than that in adjacent tissues (11.3% vs 93.8%, χ²=109.173, P<0.05). The expressions of BMP4 and Smad4 protein in PTC patients were correlated with the tumor size, TNM stage, lymph node metastasis, degree of infiltration and multiple foci (P<0.05).Conclusions The expression levels of BMP4 mRNA and Smad4 mRNA in PTC tissues are decreased, and the expression of BMP4 protein and Smad4 protein are closely related to tumor size, TNM stage and lymph node metastasis, which may be used as new therapeutic targets.

Citation： WANG Zongyue, ZHANG Wanyue, MENG FanJie, GE Wanling, LIU Chuanliang, YUAN Qingling. Correlation between the expressions of BMP4, Smad4 and clinicopathological features in papillary thyroid carcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2021, 28(12): 1587-1592. doi: 10.7507/1007-9424.202104025 Copy

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2.	黄韬, 胡丽丽, 周军. 难治性分化型甲状腺癌的研究进展. 东南大学学报(医学版), 2017, 36(5): 876-881.
3.	Prete A, Borges de Souza P, Censi S, et al. Update on fundamental mechanisms of thyroid cancer. Front Endocrinol (Lausanne), 2020, 11(1): 102-107.
4.	王俊起. 分化型甲状腺癌的诊疗进展. 实用医学杂志, 2019, 35(20): 3258-3263.
5.	Xi G, Best B, Mania-Farnell B, et al. Therapeutic potential for bone morphogenetic protein 4 in human malignant glioma. Neoplasia, 2017, 19(4): 261-270.
6.	Gomez-Puerto MC, Iyengar PV, García de Vinuesa A, et al. Bone morphogenetic protein receptor signal transduction in human disease. J Pathol, 2019, 247(1): 9-20.
7.	Martínez VG, Rubio C, Martínez-Fernández M, et al. BMP4 induces M2 macrophage polarization and favors tumor progression in bladder cancer. Clin Cancer Res, 2017, 23(23): 7388-7399.
8.	Xue D, Sun JL, Yang J. Early L-T4 intervention improves fetal heart development in pregnant rats with subclinical hypothyroidism rats by activating BMP4/Smad4 signaling pathway. BMC Cardiovasc Disord, 2020, 20(1): 369.
9.	Yu C, Zhang L, Luo D, et al. MicroRNA-146b-3p promotes cell metastasis by directly targeting NF2 in human papillary thyroid cancer. Thyroid, 2018, 28(12): 1627-1641.
10.	李兴睿, 徐滔. 美国癌症联合委员会第 8 版分化型甲状腺癌 TNM 分期更新解读. 临床外科杂志, 2019, 27(1): 33-35.
11.	中国抗癌协会甲状腺癌专业委员会(CATO). 甲状腺微小乳头状癌诊断与治疗中国专家共识(2016 版). 中国肿瘤临床, 2016, 43(10): 405-411.
12.	Kartal K, Aygün N, Uludağ M. Clinicopathologic differences between micropapillary and papillary thyroid carcinoma. Sisli Etfal Hastan Tip Bul, 2019, 53(2): 120-124.
13.	陈锐, 陈创, 王耀槐, 等. 甲状腺微小乳头状癌不同年龄段的临床病理特点比较. 临床外科杂志, 2017, 25(11): 846-849.
14.	So YK, Kim MJ, Kim S, et al. Lateral lymph node metastasis in papillary thyroid carcinoma: A systematic review and meta-analysis for prevalence, risk factors, and location. Int J Surg, 2018, 50: 94-103.
15.	Choi S, Yu J, Park A, et al. BMP-4 enhances epithelial mesenchymal transition and cancer stem cell properties of breast cancer cells via Notch signaling. Sci Rep, 2019, 9(1): 11724.
16.	Zhang J, Luo A, Huang F, et al. SERPINE2 promotes esophageal squamous cell carcinoma metastasis by activating BMP4. Cancer Lett, 2020, 469(1): 390-398.
17.	Deng G, Chen Y, Guo C, et al. BMP4 promotes the metastasis of gastric cancer by inducing epithelial-mesenchymal transition via ID1. J Cell Sci, 2020, 133(11): jcs237222.
18.	Zhao M, Mishra L, Deng CX. The role of TGF-β/SMAD4 signaling in cancer. Int J Biol Sci, 2018, 14(2): 111-123.
19.	姚磊, 林雨佳, 高爽, 等. miR-34a 通过调控 TGF-β/Smad4 信号通路激活自噬而降低结肠癌细胞对奥沙利铂的耐药性. 中国普外基础与临床杂志, 2018, 25(6): 680-688.
20.	瞿根义, 张玉龙, 徐勇, 等. FOXO1 和 Smad4 对前列腺癌增殖和转移的协同抑制作用. 临床与病理杂志, 2020, 40(7): 1625-1631.
21.	Thomsen LH, Fog-Tonnesen M, Nielsen Fink L, et al. Disparate phospho-Smad2 levels in advanced type 2 diabetes patients with diabetic nephropathy and early experimental db/db mouse model. Ren Fail, 2017, 39(1): 629-642.
22.	Cyr-Depauw C, Northey JJ, Tabariès S, et al. Chordin-Like 1 suppresses bone morphogenetic protein 4-induced breast cancer cell migration and invasion. Mol Cell Biol, 2016, 36(10): 1509-1525.
23.	Jiramongkolchai P, Owens P, Hong CC. Emerging roles of the bone morphogenetic protein pathway in cancer: potential therapeutic target for kinase inhibition. Biochem Soc Trans, 2016, 44(4): 1117-1134.
24.	Xie H, Liu M, Jin Y, et al. miR-1323 suppresses bone mesenchymal stromal cell osteogenesis and fracture healing via inhibiting BMP4/SMAD4 signaling. J Orthop Surg Res, 2020, 15(1): 237.
25.	Eckhardt BL, Cao Y, Redfern AD, et al. Activation of canonical BMP4-SMAD7 signaling suppresses breast cancer metastasis. Cancer Res, 2020, 80(6): 1304-1315.

1. Rusinek D, Krajewska J, Jarząb M. Mouse models of papillary thyroid carcinoma—short review. Endokrynol Pol, 2016, 67(2): 212-223.
2. 黄韬, 胡丽丽, 周军. 难治性分化型甲状腺癌的研究进展. 东南大学学报(医学版), 2017, 36(5): 876-881.
3. Prete A, Borges de Souza P, Censi S, et al. Update on fundamental mechanisms of thyroid cancer. Front Endocrinol (Lausanne), 2020, 11(1): 102-107.
4. 王俊起. 分化型甲状腺癌的诊疗进展. 实用医学杂志, 2019, 35(20): 3258-3263.
5. Xi G, Best B, Mania-Farnell B, et al. Therapeutic potential for bone morphogenetic protein 4 in human malignant glioma. Neoplasia, 2017, 19(4): 261-270.
6. Gomez-Puerto MC, Iyengar PV, García de Vinuesa A, et al. Bone morphogenetic protein receptor signal transduction in human disease. J Pathol, 2019, 247(1): 9-20.
7. Martínez VG, Rubio C, Martínez-Fernández M, et al. BMP4 induces M2 macrophage polarization and favors tumor progression in bladder cancer. Clin Cancer Res, 2017, 23(23): 7388-7399.
8. Xue D, Sun JL, Yang J. Early L-T4 intervention improves fetal heart development in pregnant rats with subclinical hypothyroidism rats by activating BMP4/Smad4 signaling pathway. BMC Cardiovasc Disord, 2020, 20(1): 369.
9. Yu C, Zhang L, Luo D, et al. MicroRNA-146b-3p promotes cell metastasis by directly targeting NF2 in human papillary thyroid cancer. Thyroid, 2018, 28(12): 1627-1641.
10. 李兴睿, 徐滔. 美国癌症联合委员会第 8 版分化型甲状腺癌 TNM 分期更新解读. 临床外科杂志, 2019, 27(1): 33-35.
11. 中国抗癌协会甲状腺癌专业委员会(CATO). 甲状腺微小乳头状癌诊断与治疗中国专家共识(2016 版). 中国肿瘤临床, 2016, 43(10): 405-411.
12. Kartal K, Aygün N, Uludağ M. Clinicopathologic differences between micropapillary and papillary thyroid carcinoma. Sisli Etfal Hastan Tip Bul, 2019, 53(2): 120-124.
13. 陈锐, 陈创, 王耀槐, 等. 甲状腺微小乳头状癌不同年龄段的临床病理特点比较. 临床外科杂志, 2017, 25(11): 846-849.
14. So YK, Kim MJ, Kim S, et al. Lateral lymph node metastasis in papillary thyroid carcinoma: A systematic review and meta-analysis for prevalence, risk factors, and location. Int J Surg, 2018, 50: 94-103.
15. Choi S, Yu J, Park A, et al. BMP-4 enhances epithelial mesenchymal transition and cancer stem cell properties of breast cancer cells via Notch signaling. Sci Rep, 2019, 9(1): 11724.
16. Zhang J, Luo A, Huang F, et al. SERPINE2 promotes esophageal squamous cell carcinoma metastasis by activating BMP4. Cancer Lett, 2020, 469(1): 390-398.
17. Deng G, Chen Y, Guo C, et al. BMP4 promotes the metastasis of gastric cancer by inducing epithelial-mesenchymal transition via ID1. J Cell Sci, 2020, 133(11): jcs237222.
18. Zhao M, Mishra L, Deng CX. The role of TGF-β/SMAD4 signaling in cancer. Int J Biol Sci, 2018, 14(2): 111-123.
19. 姚磊, 林雨佳, 高爽, 等. miR-34a 通过调控 TGF-β/Smad4 信号通路激活自噬而降低结肠癌细胞对奥沙利铂的耐药性. 中国普外基础与临床杂志, 2018, 25(6): 680-688.
20. 瞿根义, 张玉龙, 徐勇, 等. FOXO1 和 Smad4 对前列腺癌增殖和转移的协同抑制作用. 临床与病理杂志, 2020, 40(7): 1625-1631.
21. Thomsen LH, Fog-Tonnesen M, Nielsen Fink L, et al. Disparate phospho-Smad2 levels in advanced type 2 diabetes patients with diabetic nephropathy and early experimental db/db mouse model. Ren Fail, 2017, 39(1): 629-642.
22. Cyr-Depauw C, Northey JJ, Tabariès S, et al. Chordin-Like 1 suppresses bone morphogenetic protein 4-induced breast cancer cell migration and invasion. Mol Cell Biol, 2016, 36(10): 1509-1525.
23. Jiramongkolchai P, Owens P, Hong CC. Emerging roles of the bone morphogenetic protein pathway in cancer: potential therapeutic target for kinase inhibition. Biochem Soc Trans, 2016, 44(4): 1117-1134.
24. Xie H, Liu M, Jin Y, et al. miR-1323 suppresses bone mesenchymal stromal cell osteogenesis and fracture healing via inhibiting BMP4/SMAD4 signaling. J Orthop Surg Res, 2020, 15(1): 237.
25. Eckhardt BL, Cao Y, Redfern AD, et al. Activation of canonical BMP4-SMAD7 signaling suppresses breast cancer metastasis. Cancer Res, 2020, 80(6): 1304-1315.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Correlation between the expressions of BMP4, Smad4 and clinicopathological features in papillary thyroid carcinoma

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