Although radiotherapy has been successfully applied to treat many cancer types, surviving cancer cells often acquire therapeutic resistance, leading to increased risk of local recurrence and distant metastases via modification of the tumor microenvironment. Previously, we reported that high expression of Bcl-w in cancer patients is significantly correlated with poor survival as well as malignant activity. However, the relationship between ionizing radiation (IR)-induced resistance and Bcl-w expression in cancer cells is currently unclear. We showed that IR-induced Bcl-w contributes to EMT (epithelial-mesenchymal transition), migration, angiogenesis, stemness maintenance, and metastasis by promoting the expression of factors related to these phenotypes, both in vitro and in vivo. Meanwhile, IR enhanced hypermethylation of miR-205-5p CpG islands through Src activation, leading to decreased miR-205-5p expression and, in turn, potentially stimulating Bcl-w-mediated malignant activity and metastasis. The clinical applicability of Bcl-w and miR-205-5p from cells or animal models was confirmed using tissues and plasma of breast carcinoma patients. Based on the collective findings, we propose that miR-205-5ps as important negative mediators of resistance in radiotherapy could serve as useful potential targets of concurrently applied genetic therapy aimed to inhibit tumor aggressiveness and enhance the efficiency of radiotherapy in cancer patients.

尽管放射疗法已成功地应用于治疗多种类型的癌症，但存活的癌细胞通常具有治疗抗性，从而通过改变肿瘤微环境而导致局部复发和远处转移的风险增加。以前，我们报道癌症患者中Bcl-w的高表达与不良的生存率以及恶性活动密切相关。但是，目前尚不清楚电离辐射（IR）诱导的耐药性与癌细胞中Bcl-w表达之间的关系。我们表明，IR诱导的Bcl-w通过促进体外和体内与这些表型相关的因子的表达而促进EMT（上皮-间质转化），迁移，血管生成，干性维持和转移。同时，IR通过Src激活增强了miR-205-5p CpG岛的甲基化，导致miR-205-5p表达降低，进而可能刺激Bcl-w介导的恶性活动和转移。使用乳腺癌患者的组织和血浆证实了来自细胞或动物模型的Bcl-w和miR-205-5p的临床适用性。基于集体的发现，我们建议miR-205-5ps作为放射治疗中重要的负性抗性介体，可以作为同时应用基因治疗的有用潜在靶标，旨在抑制肿瘤的侵袭性并提高癌症患者的放射治疗效率。