T-Box Transcription Factor 22 Is an Immune Microenvironment-Related Biomarker Associated With the BRAF V600E Mutation in Papillary Thyroid Carcinoma.

Xubin Dong,Jing Hu,Xiaohua Zhang,Cheng Zheng,Jingjing Song,Haiguang Liu

doi:10.3389/fcell.2020.590898

Abstract

Papillary thyroid cancer (PTC) is the most common malignant disease in endocrine systems. T-box transcription factor 22 (TBX22) is a phylogenetically conserved family member that has not been widely characterized in cancers. In this study, we explored the potential clinical significance and biological functions of TBX22 in PTC. Comprehensive analyses of TBX22 were based on the public databases and our local qRT-PCR cohort. We observed that TBX22 was significantly downregulated in PTC compared with normal tissues. TBX22 was associated with several clinicopathological factors in PTC. Low TBX22 expression correlated with BRAFV600E and TERT mutation. Functional enrichment analysis revealed that cancer-related pathways and immune progress were closely associated with TBX22 in PTC. In TBX22-low PTC, high immune infiltration levels with increased CD8+ T cells, natural killer, M1 macrophages, and T-regulatory cells were observed. TBX22 was negatively correlated with the activity of different steps of the anticancer immunity cycle. Functionally, overexpression of TBX22 inhibited the proliferation, invasion, and migration in PTC cells, while knocking down of TBX22 showed the opposite effects. The present findings disclose that TBX22, as an immune microenvironment-related biomarker, could be an important tumor suppresser gene and might inform the management of PTC patients better.

Highlights

According to the origin of cells, thyroid cancers are classified into follicular-derived and C-cell-derived
For papillary thyroid cancer (PTC) patients (TCGA cohort), T-box transcription factor 22 (TBX22) was significantly lower in PTC than in the corresponding normal thyroid tissue (Figure 1A, p < 0.0001), which was compatible in the GSE33630, GSE60542, and GSE5364 cohorts (Figures 1B–D, all p < 0.0001)
To validate the transcription level of TBX22 in our local PTC patients, we performed qRT-polymerase chain reaction (PCR) of 79 pairs of tumor samples and adjacent normal thyroid tissues, and TBX22 was downregulated in PTC tissues compared with that in adjacent normal tissues (Figure 1E, p < 0.0001)

Summary

Introduction

According to the origin of cells, thyroid cancers are classified into follicular-derived and C-cell-derived. Over the past several decades, the rising incidence of PTC has been reported, making it an increasingly important health tissue in most populations of the world (James et al, 2018). Clinical and pathologic factors associated with a somewhat higher risk for PTC recurrence and cancerrelated mortality include older age at diagnosis, size of the primary tumor, and the presence of soft-tissue invasion or distant metastases (Johnson et al, 1988; Asioli et al, 2010; Randolph et al, 2012). The prognosis is poorer in patients with specific subtypes of PTC, including tall cell and hobnail variants (Yoo et al, 2016). PTC patients had a favorable overall prognosis, and cancer-specific mortality in non-metastatic PTC patients was only 6% (Ghossein and Livolsi, 2008). Existing treatments do not sufficiently improve the prognosis of more aggressive and lethal dedifferentiated PTCs

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