Induction of CXCL8 by endoplasmic reticulum stress promotes migration and invasion of esophageal squamous cell carcinoma through activation of SMAD2/3

Endoplasmic reticulum stress (ERS) is a protective stress response aimed at mitigating its own abnormal proteins, which is closely associated with tumors. However, the molecular mechanism of ERS in the pathogenesis of esophageal squamous cell carcinoma (ESCC) remains unclear. In the present study, RNA Sequencing was carried out in the ESCC ERS cell model in vitro, and differentially expressed genes were screened, among which CXCL8 with exhibited differential expression which was studied. CXCL8 was significantly upregulated after thapsigargin (TG; an ERS inducer) treatment in ESCC cells. A marked elevated expression of CXCL8 and its receptors were observed in ESCC cells. CXCL8 was induced by the IRE1α and PERK pathways of ERS, transcription of which was activated by the downstream transcription factors XBP1 and ATF4. TG and rh‑CXCL8 facilitated migration and invasion of ESCC cells, and the migration and invasion effect of TG on ESCC cells could be partially prevented by knockdown of CXCR1. Furthermore, CXCL8‑CXCR1 could activate SMAD2/3 and the activation of SMAD2/3 directly or indirectly regulated the transcription of SNAI2 and ZEB1 to promote the progression of epithelial‑mesenchymal transition (EMT) in ESCC. Both in vivo experiments and immunohistochemical analyses further demonstrated the oncogenic effects of CXCL8. In conclusion, the data obtained in the present study indicated that CXCL8 may be induced via the IRE1α/XBP1 and PERK/ATF4 pathways, and that the CXCL8‑CXCR1/2‑SMAD2/3‑SNAI2/ZEB1 axis is involved in the EMT process of ER‑stressed ESCC cells. Thus, blocking the CXCL8‑CXCR1/2 axis may disrupt ERS‑induced migration and invasion of ESCC cells, thereby improving the prognosis of patients with ESCC.

C‑X‑C motif chemokine ligand 8; SMAD2/3; endoplasmic reticulum stress; esophageal squamous cell carcinoma.