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The emerging role of transcription factor FOXP3 in thyroid cancer

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Abstract

Transcription factor FOXP3 is a crucial regulator in the development and function of regulatory T cells (Treg) that are essential for immunological tolerance and homeostasis. Numerous studies have indicated the correlation of tumor infiltrating FOXP3+ Treg upregulation with poor prognostic parameters in thyroid cancer, including lymph node metastases, extrathyroidal extension, and multifocality. Most immune-checkpoint molecules are expressed in Treg. The blockage of such signals with checkpoint inhibitors has been approved for several solid tumors, but not yet for thyroid cancer. Thyroid abnormalities may be induced by checkpoint inhibitors. For example, hypothyroidism, thyrotoxicosis, painless thyroiditis, or even thyroid storm are more frequently associated with anti-PD-1 antibodies (pembrolizumab and nivolumab). Therefore, Targeting FOXP3+ Treg may have impacts on checkpoint molecules and the growth of thyroid cancer. Several factors may impact the role and stability of FOXP3, such as alternative RNA splicing, mutations, and post-translational modification. In addition, the role of FOXP3+ Treg in the tumor microenvironment is also affected by the complex regulatory network formed by FOXP3 and its transcriptional partners. Here we discussed how the expression and function of FOXP3 were regulated and how FOXP3 interacted with its targets in Treg, aiming to help the development of FOXP3 as a potential therapeutic target for thyroid cancer.

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Abbreviations

ATC:

anaplastic thyroid cancer

BRAF:

B-type Raf kinase

CNS2:

Conserved noncoding sequence 2

FTC:

follicular thyroid cancer

HAT:

histone acetyltransferases

HDACs:

histone/protein deacetylases

hnRNPF:

heterogeneous nuclear ribonucleoprotein

IFN-γ:

interferon-gamma

IPEX:

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

iTreg:

inducible Treg

MALT:

mucosa-associated lymphoid tissue

MNG:

multinodular goiter

MTC:

medullary thyroid cancer

NFAT:

nuclear factor of activated T-cells

pDCs:

plasmacytoid dendritic cells

PD-L1:

programmed death-ligand 1

PTC:

papillary thyroid cancer

PTM:

Post-translation modification

PTMC:

papillary thyroid microcarcinoma

qRRM:

quasi-RNA recognition motif

RUNX:

runt-related transcription factor

Tet2:

ten-eleven-translocation 2

Treg:

regulatory T cells

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Funding

This study was supported by grants from the Research Grants Council of the Hong Kong Special Administrative Region (No. 14109516), the National Natural Science Foundation of China (No.81472339).

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  1. Zhongqin Gong and Hao Jia equally contributed to this work.

Authors and Affiliations

  1. Department of Otorhinolaryngology, Head and Neck Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China

    Zhongqin Gong, Lingbin Xue, Michael C. F. Tong & George G. Chen

  2. Department of Thyroid and Breast Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China

    Hao Jia

  3. Shenzhen Key Laboratory of ENT, Institute of ENT & Longgang, ENT Hospital, Shenzhen, China

    Dongcai LI & Xianhai Zeng

  4. Department of Head & Neck Surgery, Cancer Hospital Chinese Academy of Medical Sciences, Shenzhen Center, Shenzhen, Guangdong, China

    Minghui Wei

  5. Department of Biochemistry and Molecular Biology, Faculty of Basic Medical Sciences, Chongqing Medical University, Chongqing, China

    Zhimin Liu

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  1. Zhongqin Gong
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Gong, Z., Jia, H., Xue, L. et al. The emerging role of transcription factor FOXP3 in thyroid cancer. Rev Endocr Metab Disord 23, 421–429 (2022). https://doi.org/10.1007/s11154-021-09684-8

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