The expression and methylation of PITX genes is associated with the prognosis of head and neck squamous cell carcinoma

Yaqiong Zhao; Jie Zhao; Mengmei Zhong; Qian Zhang; Fei Yan; Yunzhi Feng; Yue Guo

doi:10.3389/fgene.2022.982241

The expression and methylation of PITX genes is associated with the prognosis of head and neck squamous cell carcinoma

Front Genet. 2022 Sep 20:13:982241. doi: 10.3389/fgene.2022.982241. eCollection 2022.

Authors

Yaqiong Zhao¹, Jie Zhao¹, Mengmei Zhong¹, Qian Zhang¹, Fei Yan², Yunzhi Feng¹, Yue Guo¹

Affiliations

¹ Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, China.
² Hunan Key Laboratory of Oral Health Research and Hunan 3D Printing Engineering Research Center of Oral Care and Hunan Clinical Research Center of Oral Major Diseases and Oral Health and Xiangya Stomatological Hospital and Xiangya School of Stomatology, Central South University, Changsha, China.

Abstract

Background: The PITX gene family, comprising PITX1, PITX2, and PITX3, is critical in organogenesis and has been evolutionary conserved in animals. PITX genes are associated with the advanced progression and poor prognosis of multiple cancers. However, the relationship between the PITX genes and head and neck squamous cell carcinoma (HNSC) has not been reported. Methods: We used data from The Cancer Genome Atlas (TCGA) to analyze the association between PITX mRNA expression and clinicopathological parameters of patients with HNSC. The prognostic value of PITX genes was evaluated using the Kaplan-Meier plotter. Multivariate Cox analysis was used to screen out prognosis-associated genes to identify better prognostic indicators. The potential roles of PITX1 and PITX2 in HNSC prognosis were investigated using the protein-protein interaction (PPI) network, Gene Ontology (GO) analysis, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The correlation between PITX1 and PITX2 expression or methylation and immune cell infiltration was evaluated using the tumor-immune system interaction database (TISIDB). MethSurv was used to identify DNA methylation and its effect on HNSC prognosis. Results: PITX genes expression was correlated with different cancers. PITX1 and PITX2 expression was lower in the patients with HNSC. In HNSC, PITX1 expression was significantly related to the clinical stage, histologic grade, and N stage, while PITX2 expression was only significantly related to the histologic grade. The high expression of PITX3 was significantly related to the histologic grade, T stage, and N stage. Survival analysis revealed that PITX genes had prognostic value in HNSC, which was supported by multivariate Cox analysis. PPI network and enrichment analysis showed that the genes interacting with PITX1 and PITX2 belonged predominantly to signaling pathways associated with DNA binding and transcription. Of the CpG DNA methylation sites in PITX1 and PITX2, 28 and 22 were related to the prognosis of HNSC, respectively. Additionally, PITX1 and PITX2 expression and methylation was associated with tumor-infiltrating lymphocytes (TILs). Conclusion: The PITX genes were differentially expressed in patients with HNSC, highlighting their essential role in DNA methylation and tumor-infiltrating immune cell regulation, as well as overall prognostic value in HNSC.

Keywords: Bioinformatic analysis; DNA Methylation; HNSC; PITX gene family; prognosis.