TFAP2B overexpression contributes to tumor growth and progression of thyroid cancer through the COX-2 signaling pathway

Xiaoyan Fu,Huayong Zhang,Dingbo Shi,Wuguo Deng,Tianrun Liu,Xuan Su,Fan Yao,Ankui Yang,Weichao Chen,Zhongyuan Yang,Zhipeng Chen,Miao Chen

doi:10.1038/s41419-019-1600-7

Abstract

Thyroid cancer is commonly seen in the clinic with a rapidly increasing incidence globally. COX-2 overexpression correlates with the pathologic type of thyroid carcinoma, and it has been suggested that COX-2 overexpression is associated with a poor prognosis. However, little is known about its upstream regulatory mechanism. Bioinformatics suggested that transcription factor AP-2 beta (TFAP2B) might specifically bind to the COX-2 promoter, which was confirmed by biotin-labeled COX-2 promoter pulldown and luciferase reporter assays. We performed western blot and immunohistochemical staining to detect the expression of TFAP2B/COX-2 in thyroid cancer tissues (T) and the matched adjacent noncarcinoma tissues (ANT), and investigated the relationship between TFAP2B/COX-2 expression and clinical pathological factors in thyroid cancer patients. Afterward, MTS, colony formation, cell-apoptosis assay, transwell-invasion and scratch assays were performed to examine the proliferation, apoptosis, invasion, and migration of thyroid cancer cells with TFAP2B knocked down or overexpressed. The mouse xenograft experiment was performed to study in vivo the proliferation of thyroid cancer cells with TFAP2B knocked down or overexpressed. We found that TFAP2B bound to the promoter of COX-2 to activate its expression. Western blot and immunohistochemistry showed that TFAP2B/COX-2 was highly expressed in thyroid cancer, and high TFAP2B and COX-2 expression was associated with aggressive clinicopathological features in thyroid cancer. TFAP2B mediated thyroid cancer cell proliferation, apoptosis, invasion, and migration via the COX-2 signaling pathway in vitro and in vivo. TFAP2B bound to the promoter of COX-2 to activate its expression, indicating that TFAP2B is a critical regulatory molecule in the COX-2 signaling pathway that promoted tumor progression in thyroid cancer.

Highlights

As an endocrine malignancy, thyroid cancer is commonly seen in the clinical, and has rapidly increased in global incidence in recent decades[1]
By querying the TRANSFAC database, we found that transcription factor AP-2 beta (TFAP2B) may be a binding protein that combines with COX-2 promoter regions
As the results are shown above, we found that TFAP2B/COX-2 expression is likely connected with invasion and metastasis in thyroid cancer Bold values indicated statistic significance nude mice with thyroid cancer cells stably expressing TFAP2B-shRNAs or the control shRNAs and stably expressing TFAP2B or the control vector

Summary

Introduction

Thyroid cancer is commonly seen in the clinical, and has rapidly increased in global incidence in recent decades[1]. The average annual increase in thyroid cancer incidence (6.6%) between 2000 and 2009 is the highest among all cancers in the United States[2]. Thyroid cancers such as papillary thyroid cancer (PTC) have favorable prognosis and a low death rate, a certain number of patients develop a more aggressive forms that is unresponsive to radioactive iodine and chemotherapy[3], resulting in increased incurability. In previous studies, upregulated COX-2 expression has been observed in a number of malignant tumors, such as breast cancer and colon cancers[4,5]. We do not know much about its upstream regulatory mechanism

Methods

Results

Conclusion