Lung cancer is one of the most common reasons for cancer-induced mortality across the globe, despite major advancements in the treatment strategies including radiotherapy and chemotherapy. Existing reports suggest that CXCR4 is frequently expressed by malignant tumor and is imperative for vascularization, tumor growth, cell migration, and metastasis pertaining to poor prognosis. In this study, we infer that CXCR4 confers resistance to ionizing radiation (IR) in nonsmall cell lung cancer (NSCLC) cells. Further, on the basis of colony forming ability, one finds that drug-resistant A549/GR cells with improved CXCR4 expression exhibited more resistance to IR than A549 cells evidenced along with a reduction in the formation of γ-H2AX foci after IR. Transfection of shRNA against CXCR4 or treatment of pharmacological inhibitor (AMD3100) both led to sensitization of A549/GR cells towards IR. Conversely, the overexpression of CXCR4 in A549 and H460 cell lines was found to improve clonogenic survival, and reduce the formation of γ-H2AX foci after IR. CXCR4 expression was further correlated with STAT3 activation, and suppression of STAT3 activity with siSTAT3 or a specific inhibitor (WP1066) significantly stymied the colony-forming ability and increased γ-H2AX foci formation in A549/GR cells, indicating that CXCR4-mediated STAT3 signaling plays an important role for IR resistance in NSCLC cells. Finally, CXCR4/STAT3 signaling was mediated with the upregulation of Slug and downregulation of the same with siRNA, which heightened IR sensitivity in NSCLC cells. Our data collectively suggests that CXCR4/STAT3/Slug axis is paramount for IR resistance of NSCLC cells, and can be regarded as a therapeutic target to enhance the IR sensitivity of this devastating cancer.

尽管放疗和化疗等治疗策略取得了重大进展，但肺癌仍是全球范围内导致癌症死亡的最常见原因之一。现有报告表明，CXCR4 经常在恶性肿瘤中表达，并且对于血管形成、肿瘤生长、细胞迁移和与预后不良相关的转移是必不可少的。在这项研究中，我们推断 CXCR4 赋予非小细胞肺癌 (NSCLC) 细胞对电离辐射 (IR) 的抵抗力。此外，基于集落形成能力，人们发现具有改善的 CXCR4 表达的耐药 A549/GR 细胞表现出比 A549 细胞更多的 IR 抗性，这证明了 IR 后 γ-H2AX 病灶的形成减少。针对 CXCR4 的 shRNA 转染或药物抑制剂 (AMD3100) 的处理均导致 A549/GR 细胞对 IR 敏感。相反，发现在 A549 和 H460 细胞系中过表达 CXCR4 可提高克隆存活率，并减少 IR 后 γ-H2AX 病灶的形成。CXCR4 表达进一步与 STAT3 激活相关，用 siSTAT3 或特定抑制剂 (WP1066) 抑制 STAT3 活性显着阻碍了 A549/GR 细胞的集落形成能力并增加了 γ-H2AX 病灶的形成，表明 CXCR4 介导的 STAT3 信号传导在 NSCLC 细胞中对 IR 抗性起重要作用。最后，CXCR4/STAT3 信号通过 Slug 的上调和 siRNA 的下调介导，这提高了 NSCLC 细胞中的 IR 敏感性。