The role of γH2AX and H2AX in cervical carcinogenesis, invasion, and metastasis, and their relationship with the expression of E-cadherin

Background: Our previous studies found a link between increased γH2AX expression and cervical carcinogenesis. However, the roles and relationships of γH2AX and its precursor protein, H2AX, in carcinogenesis, invasion, and metastasis of cervical cancer, as well as their association with epithelial-mesenchymal transition (EMT), remain unclear. Methods: The expression of H2AX, γH2AX and the EMT marker E-cadherin was assessed through immunohistochemical staining in 66 cases of cervical intraepithelial neoplasia (CIN) and 87 cases of primary squamous cell carcinoma (SCC). Furthermore, the expression of H2AX, γH2AX and E-cadherin was evaluated in tumor budding (78 patients), tumor emboli (18 patients), or lymph node metastases (16 patients), along with their corresponding central tumors in the same SCC patients. Lastly, the correlation between the expression of γH2AX and H2AX in central tumors, tumor budding, and the clinicopathological characteristics of patients was investigated. Results: In CIN and SCC, the expression of γH2AX is upregulated as the severity of the disease, while the expression of H2AX and E-cadherin is downregulated. In tumor budding, tumor emboli, and metastatic lymph nodes, γH2AX expression is significantly higher than in the central tumor, while H2AX expression is significantly lower. The expression of E-cadherin is significantly lower in tumor budding and tumor emboli, compared to the central tumor. Conversely, the expression of E-cadherin in lymph nodes is significantly higher than in tumor budding. γH2AX expression in tumor budding is associated with FIGO staging, tumor emboli, and menopausal status. Conclusions: γH2AX and H2AX play significant roles in the processes of carcinogenesis, invasion, and metastasis in cervical cancer. Moreover, H2AX may potentially promote cervical cancer invasion and metastasis through its involvement in the EMT, while γH2AX does not participate in this process. Clnical Trial Registration: ChiCTR-TRC-1800016405.

Cervical squamous cell carcinoma; Cervical intraepithelial neoplasia; Phosphorylated H2AX; Histone H2AX; EMT; DNA double-strand damage

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