Loss of ID3 drives papillary thyroid cancer metastasis by targeting E47-mediated epithelial to mesenchymal transition

Sunwang Xu,Caiqin Mo,Xiangjin Chen,Ling Chen,Huihao Zhang,Yixing Yan,Junyu Lin,Kunlin Wu,Xiaoyu Liu,Youzhi Zhu

doi:10.1038/s41420-021-00614-w

Abstract

Papillary thyroid cancer (PTC) is the main histological type of thyroid cancer and accounts for almost all increased cases worldwide. Patients with PTC exhibit a favorable prognosis, but the fact that PTC is often accompanied by a high prevalence of lymph node metastasis (LNM) means that the overall recurrence-free survival rate in PTC patients is relatively low. Herein, we identified that ID3 expression is subdued in PTC tissues and closely associated with LNM and a poor disease-free survival outcome in PTC patients. The main contributor to this gene repression is the hypermethylation of the CpG island at the promoter of ID3. Besides, we uncovered that a loss of ID3 promotes invasion and migration of PTC cells, while an ectopic overexpression of ID3 inhibits invasion and migration. Mechanistically, ID3 exhibits tumor suppressor functions in PTC cells by interacting with E47 to form heterodimers that prevent E47 binding to CDH1 promoter and maintaining CDH1 transcription and epithelial phenotype in PTC cells. Taken together, our study demonstrates that ID3 plays a tumor suppressor role in PTC and impedes metastasis by inhibiting E47-mediated epithelial to mesenchymal transition.

Highlights

Over the past decades, the incidence of thyroid cancer has been rapidly increasing worldwide, with the papillary thyroid cancer (PTC) subtype accounting for almost all the increased cases [1]
ID3 is downregulated in PTC and lymph node metastasis (LNM) tissues To characterize the expression pattern of inhibitor of DNA-binding (ID) proteins in PTC tissues, we first analyzed the ID1–4 expression profiles in thyroid cancer obtained from The Cancer Genome Atlas (TCGA) and The
We demonstrate that ID3 is significantly downregulated in tumorous and LNM tissues of PTC and that ID3 inhibition is associated with PTC metastasis and poor survival outcomes

Summary

Introduction

The incidence of thyroid cancer has been rapidly increasing worldwide, with the papillary thyroid cancer (PTC) subtype accounting for almost all the increased cases [1]. PTC is the major histological type of thyroid cancer, accounting for over 90% of cases. PTC derives from thyroid follicular cells and is generally iodine-avid, meaning it is amenable and can usually be cured by surgery with or without the combination of radioactive iodine ablation [2]. PTC exhibits a gentle tumor biological behavior accompanied by a low disease-specific mortality rate. Cervical lymph node metastasis (LNM) is associated with an increased mortality risk in PTC patients [4]. There is an urgent need to uncover the molecular mechanisms and establish potential therapeutic targets to overcome PTC metastasis

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Conclusion