Prognostic biomarker GSTK1 in head and neck squamous cell carcinoma and its correlation with immune infiltration and DNA methylation

Yao Feng; Ying-Hui Zhou; Jie Zhao; Xiao-Lin Su; Ning-Xin Chen; Ya-Qiong Zhao; Qin Ye; Jing Hu; Ze-Yue Ou-Yang; Meng-Mei Zhong; Yi-Fan Yang; Peng-Ju Han; Yue Guo; Yun-Zhi Feng

doi:10.3389/fgene.2023.1041042

Prognostic biomarker GSTK1 in head and neck squamous cell carcinoma and its correlation with immune infiltration and DNA methylation

Front Genet. 2023 Mar 3:14:1041042. doi: 10.3389/fgene.2023.1041042. eCollection 2023.

Authors

Yao Feng¹, Ying-Hui Zhou^{1

2}, Jie Zhao¹, Xiao-Lin Su¹, Ning-Xin Chen¹, Ya-Qiong Zhao¹, Qin Ye¹, Jing Hu¹, Ze-Yue Ou-Yang¹, Meng-Mei Zhong¹, Yi-Fan Yang³, Peng-Ju Han⁴, Yue Guo¹, Yun-Zhi Feng¹

Affiliations

¹ Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
² National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
³ Xiangya School of Stomatology, Central South University, Changsha, China.
⁴ College of Life Sciences, Sichuan University, Chengdu, Sichuan, China.

Abstract

Background: Glutathione S-transferase kappa 1 (GSTK1) is critical in sarcoma and breast cancer (BRCA) development. However, the clinical significance of GSTK1 in head and neck squamous cell carcinoma (HNSC) remains unclear. This study is the first investigation into the role of GSTK1 in HNSC. Methods: All original data were downloaded from the Cancer Genome Atlas (TCGA) dataset and verified by R Base Package 4.2.0. The expression of GSTK1 in various cancers was explored with TIMER and TCGA databases. Prognostic value of GSTK1 was analyzed via survival module of Kaplan-Meier plotter and Human Protein Atlas database and Cox regression analysis. The association between GSTK1 and clinical features was evaluated by Wilcoxon signed-rank test and logistic regression analysis. The relationship between GSTK1 and immune infiltration and methylation level was further explored. The expression of GSTK1 and its correlation with immune cell infiltration was verified by Immunohistochemical staining (IHC). Results: GSTK1 was lower in HNSC, BRCA, Lung squamous cell carcinoma, and Thyroid carcinoma than in para-carcinoma. Low GSTK1 expression was associated with worse overall survival in Bladder urothelial carcinoma, Kidney renal papillary cell carcinoma, BRCA, and HNSC. However, only in BRCA and HNSC, GSTK1 expression in tumors was lower than that in normal tissues. Cox regression analyses confirmed that GSKT1 was an independent prognostic factor of overall survival in HNSC patients. The decrease in GSTK1 expression in HNSC was significantly correlated with high T stage and smoker history. IHC showed that the expression level of GSTK1 in HNSC was lower than that in para-carcinoma. In addition, GSEA showed that three pathways related to immune infiltration were positively correlated, while two pathways related to DNA methylation were negatively correlated with expression of GSTK1. Further analysis showed that GSTK1 was moderately positively correlated with the infiltration level of T cells and Cytotoxic cells, which was further confirmed by IHC. The methylation level of GSTK1 was associated with prognosis in patients with HNSC. Conclusion: Low GSTK1 expression may be a potential molecular marker for poor prognosis in HNSC and provide new insight for the development of diagnostic marker or therapeutic target.

Keywords: DNA methylation; GSTK1; head and neck squamous cell carcinoma; immune infiltration; prognosis.

Grants and funding

This study was supported by the National Natural Science Foundation of China (81800788 and 81773339), Science and Technology Department of Hunan Province, China (2017WK2041, 2018SK52511 and 2022ZK4084), Scientific Research Project of Hunan Provincial Health Commission (202208043514 and B202308056340), Hunan Provincial Natural Science Foundation of China (2022JJ30062), Natural Science Foundation of Changsha City (kq2202403 and kq2202412), Fund for the Xiangya Clinical Medicine Database of Central South University (2014-ZDYZ-1-16), Education and Teaching Reform Research Project of Central South University (2020jy165-3), Research Project on Postgraduate Education and Teaching Reform of Central South University(2021JGB072), Hunan Provincial Innovation Foundation For Postgraduate (CX20220370); and The Fundamental Research Funds for the Central Universities of Central South University (2022ZZTS0913 and 2022ZZTS0912).