CXCR4 Promotes Growth and Metastasis of Esophageal Squamous Cell Carcinoma as a Critical Downstream Mediator of HIF-1α

Abstract

Background: Recent studies have shown that C-X-C chemokine receptor 4(CXCR4) plays an important role in a variety of tumours. However, its role and regulated mechanism in esophageal squamous cell carcinoma (ESCC) remain unclear. Methods: Immunohistochemistry, Western blot and qPCR were used to detect the expression of CXCR4 and HIF-1α. HIF-1α downstream target gene was detected by RNA-seq. The invasion and metastasis ability of HIF-1α/CXCR4 axis to ESCC cells were detected by transwell and animal experiments. Dual-luciferase analysis and chromatin immunoprecipitation assay showed that HIF-1α directly binds to the HRE site in the CXCR4 promoter. Findings: We showed that CXCR4 was enriched in ESCC tissues compared with corresponding normal tissues and predicted lymph node metastasis and poor prognosis. CXCR4 overexpression promotes the proliferation, migration and invasion of ESCC. In addition, we revealed that hypoxia-inducible factor-1α (HIF-1α) regulated CXCR4 expression via binding to a hypoxia response element in its promoter, and the HIF-1α-enhanced metastasis ability of ESCC cells was reversed by CXCR4 knockdown or treatment with MSX-122, a CXCR4 antagonist. Interpretation: In showing that the dysregulated HIF-1α/CXCR4 axis promotes ESCC malignancy, the results suggested that CXCR4 is a potential therapeutic target for ESCC. Funding: This research was supported by the National Natural Science Foundation of China (81772619, 82002551), the Science and Technology Project of Tianjin Municipal Health Commission (RC20119), the Bethune Charitable Foundation-Excelsior Surgical Fund (HZB-20190528-18), and the Clinical Trial Project of Tianjin Medical University (2017kylc006). Declaration of Interest: The authors declare no conflict of interest. Ethical Approval: All operations for human subjects were approved by the ethics committee of our hospital, and all patients provided informed consent. Gene Expression Omnibus (GEO) data were downloaded from the website (https://www.ncbi.nlm.nih.gov/geo/).