Homeobox A7 promotes esophageal squamous cell carcinoma progression through C‐C motif chemokine ligand 2‐mediated tumor‐associated macrophage recruitment

• Published in: Cancer science 2023-08, Vol.114 (8), p.3270-3286
• Main Authors: Feng, Anqi, He, Lingnan, Jiang, Jiakai, Chu, Yuan, Zhang, Zehua, Fang, Kang, Wang, Zeyu, Li, Zhaoxing, Sun, Mingchuang, Zhao, Ziying, Shi, Jianing, Zhang, Li, Chen, Tao, Xu, Meidong
• Format: Article
• Language: English
• Subjects: Cell Line, Tumor; Cell Movement - genetics; Cell proliferation; Cell Proliferation - genetics; Cells; Chemokines; Chemotaxis; Cholecystokinin; C‐C motif chemokine ligand 2 (CCL2); Endoscopy; Enzyme-linked immunosorbent assay; Epidermal growth factor; Epidermal Growth Factor - metabolism; epidermal growth factor receptor (EGFR); Epidermal growth factor receptors; Esophageal cancer; Esophageal carcinoma; Esophageal Neoplasms - pathology; esophageal squamous cell carcinoma (ESCC); Esophageal Squamous Cell Carcinoma - pathology; Gene Expression Regulation, Neoplastic; Genes, Homeobox; Genomes; Genomics; Homeobox; homeobox A7 (HOXA7); Humans; Laboratory animals; Leukocyte migration; Ligands; Macrophages; Malignancy; Metastases; Monocyte chemoattractant protein 1; Original; ORIGINAL ARTICLES; Pathogens; Squamous cell carcinoma; Therapeutic targets; Transcription factors; Transcription Factors - genetics; tumor immunology; Tumor Microenvironment; Tumor-Associated Macrophages - metabolism; Tumors; tumor‐associated macrophage (TAM)
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15842

Homeobox A7 (HOXA7) plays essential roles in multiple malignancies and was reported to be overexpressed in esophageal squamous cell carcinoma (ESCC). However, its functions in the ESCC tumor microenvironment remain to be explored. In this study, we showed that HOXA7 was overexpressed in ESCC among HOXA family members and correlated with tumor‐associated macrophage (TAM) infiltration both in The Cancer Genome Atlas database and ESCC clinical samples. Moreover, transactivation of C‐C motif chemokine ligand 2 (CCL2) by HOXA7 was identified (real‐time quantitative PCR [RT‐qPCR], western blot analysis, ELISA, and ChIP‐qPCR), which was detected to drive chemotaxis and M2 polarization of macrophages both in vitro (Transwell assay) and in vivo (xenograft tumors models). In addition, CCL2 triggers macrophage expression of epidermal growth factor (EGF) (RT‐qPCR and ELISA), which promotes tumor proliferation and metastasis by activating its receptor EGFR. In addition, EGF‐induced ESCC cell proliferation and migration can be abrogated by HOXA7 knockdown (CCK‐8 proliferation assay, EdU fluorescence, and Transwell assay). These results indicate a novel mechanistic role of HOXA7 in the cross‐talk between ESCC and TAMs, which could be an underlying therapeutic target for ESCC. A novel mechanism of transcription factor homeobox A7 (HOXA7) in promoting tumor‐associated macrophage infiltration and polarization, which accelerates esophageal squamous cell carcinoma (ESCC) progression. These findings indicate HOXA7 to be a potential new diagnostic and prognostic marker in ESCC.