Wu Junhong, Su Fangyu, Lu Juntao, Xu Huanchen, Yang Xia, Li Fei, Liu Lei, Guo Wei
Laboratory of Pathology, Hebei Cancer Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China.
Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China.
Mol Med Rep. 2025 Nov;32(5). doi: 10.3892/mmr.2025.13676. Epub 2025 Sep 5.
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 , 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 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.
内质网应激（ERS）是一种旨在减轻自身异常蛋白质的保护性应激反应，与肿瘤密切相关。然而，ERS在食管鳞状细胞癌（ESCC）发病机制中的分子机制仍不清楚。在本研究中，对ESCC ERS细胞模型进行了RNA测序，并筛选了差异表达基因，其中对表现出差异表达的CXCL8进行了研究。在ESCC细胞中，毒胡萝卜素（TG；一种ERS诱导剂）处理后CXCL8显著上调。在ESCC细胞中观察到CXCL8及其受体的表达明显升高。CXCL8由ERS的IRE1α和PERK途径诱导，其转录由下游转录因子XBP1和ATF4激活。TG和rh-CXCL8促进了ESCC细胞的迁移和侵袭，敲低CXCR1可部分阻止TG对ESCC细胞的迁移和侵袭作用。此外，CXCL8-CXCR1可激活SMAD2/3，SMAD2/3的激活直接或间接调节SNAI2和ZEB1的转录，以促进ESCC上皮-间质转化（EMT）的进展。实验和免疫组织化学分析均进一步证明了CXCL8的致癌作用。总之，本研究获得的数据表明，CXCL8可能通过IRE1α/XBP1和PERK/ATF4途径诱导，且CXCL8-CXCR1/2-SMAD2/3-SNAI2/ZEB1轴参与了内质网应激的ESCC细胞的EMT过程。因此，阻断CXCL8-CXCR1/2轴可能会破坏ERS诱导的ESCC细胞迁移和侵袭，从而改善ESCC患者的预后。
