Department of Thoracic Surgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China.
State Key Laboratory of Silkworm Genome Biology, The Institute of Sericulture and Systems Biology, Southwest University, Chongqing, China.
Cancer Med. 2019 Jul;8(7):3491-3501. doi: 10.1002/cam4.2213. Epub 2019 May 1.
As an inflammatory factor, IL-25 has been studied in variouscancers, but it is rarely reported in cancer chemotherapy resistance. Major vault protein (MVP), as a gene associated with lung multidrug resistance, is associated with multiple chemotherapy resistances of lung cancer. However, the relationship between IL-25 and MVP in lung cancer cells has not been studied. In this study, we found that both IL-25 and MVP were elevated expressed in cisplatin-resistant lung adenocarcinoma cell line (A549/CDDP). Silencing of IL-25 resulted in down-regulation of MVP expression and reduced cisplatin tolerance of A549/CDDP cells. Overexpression of IL-25 resulted in increase of MVP expression and the cisplatin tolerance in A549 cells. In addition, we found that the extracellular IL-25 could stimulate the expression of MVP and activate the NF-κB signaling pathway. Further, animal models also confirmed that IL-25 reduced the sensitivity of xenografts to chemotherapy. Taken together, we believe that the up-regulation of IL-25 induces MVP expression contributing to chemotherapy resistances of lung cancer cells. Our findings suggest that interference the expression of IL-25 might be potential treatment strategies for the clinical reversing the chemotherapy resistance.
作为一种炎症因子，IL-25 已在各种癌症中进行了研究，但在癌症化疗耐药性方面很少有报道。主要穹窿蛋白 (MVP) 作为与肺多药耐药相关的基因，与肺癌的多种化疗耐药性相关。然而，IL-25 与肺癌细胞中的 MVP 之间的关系尚未得到研究。在这项研究中，我们发现在顺铂耐药肺腺癌细胞系 (A549/CDDP) 中，IL-25 和 MVP 的表达均升高。IL-25 的沉默导致 MVP 表达下调，并降低 A549/CDDP 细胞对顺铂的耐受性。IL-25 的过表达导致 MVP 表达增加和 A549 细胞对顺铂的耐受性增加。此外，我们发现细胞外的 IL-25 可以刺激 MVP 的表达并激活 NF-κB 信号通路。此外，动物模型也证实，IL-25 降低了异种移植物对化疗的敏感性。综上所述，我们认为 IL-25 的上调诱导 MVP 表达，导致肺癌细胞的化疗耐药性。我们的研究结果表明，干扰 IL-25 的表达可能是逆转化疗耐药性的潜在治疗策略。
