Diagnostic and Prognostic Significances of SOX9 in Thymic Epithelial Tumor

Xiaodong Yuan; Lei Huang; Wenwu Luo; Yufei Zhao; Björn Nashan; Fazhi Yu; Yun Liu

doi:10.3389/fonc.2021.708735

Diagnostic and Prognostic Significances of SOX9 in Thymic Epithelial Tumor

Front Oncol. 2021 Oct 28:11:708735. doi: 10.3389/fonc.2021.708735. eCollection 2021.

Authors

Xiaodong Yuan¹, Lei Huang², Wenwu Luo³, Yufei Zhao⁴, Björn Nashan¹, Fazhi Yu⁵, Yun Liu⁴

Affiliations

¹ Organ Transplant Center, Department of Hepatobiliary and Transplantation Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
² Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Department of Pathology, Anhui Medical University, Hefei, China.
⁴ Department of Radiation Oncology, Anhui Provincial Cancer Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
⁵ The First Affiliated Hospital of USTC, School of Life Sciences, University of Science and Technology of China, Hefei, China.

Abstract

Background: Thymic epithelial tumors (TETs) are rare tumors originating from the thymic epithelial cells. SOX9, a member of the family of SOX (SRY-related high-mobility group box) genes, has been considered as an oncogene and therapeutic target in various cancers. However, its role in TETs remains uncertain.

Methods: Using the immunohistochemistry method, the expression of SOX9 was analyzed in TETs tissues, including 34 thymoma (8 cases with type A, 6 with type AB, 6 with type B1, 9 with type B2, and 5 with type B3 thymomas) and 20 thymic cancer tissues and the clinicopathologic and prognostic significances were evaluated. Further bioinformatics analysis of gene expression profiles of thymomas with high and low SOX9 expressions and the corresponding survival analyses were based on the thymoma cases identified in The Cancer Genome Atlas (TCGA) database, with the median expression level of SOX9 selected as cutoff.

Results: Immunohistochemistry staining showed that SOX9 was highly expressed in the nuclei of the epithelial cells of the Hassall's corpuscles and of the TET tumor cells. SOX9 expression was significantly associated with histological type and high expression indicated unfavorable clinical outcomes of thymomas. Bioinformatics analysis revealed that genes positively associated with SOX9 expression were mapped in proteoglycans in cancer, cell adhesion molecules, and molecules involved in extracellular matrix-receptor interaction and the TGF-β signaling pathway, and that genes negatively associated with SOX9 expression were mapped in molecules involved in primary immunodeficiency, the T cell receptor signaling pathway, Th17 cell differentiation, PD-L1 expression, and the PD-1 checkpoint pathway in cancer. In addition, SOX9 expression was positively associated with POU2F3 and TRPM5 expressions, the master regulators of tuft cells, suggesting that high SOX9 expression might be associated with the tuft cell phenotype of thymomas. Moreover, high SOX9 expression was associated with immune dysregulation of thymoma, and M2 macrophage significantly dominated in the high SOX9 expression group.

Conclusion: SOX9 may serve as a diagnostic and prognostic marker for TETs. Notably, high SOX9 expression in TETs may indicate a tuft cell phenotype and an immune suppressive microenvironment of thymomas.

Keywords: POU2F3; SOX9; thymic epithelial tumor; tuft cell; tumor microenvironment.