Abstract
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.
Highlights
Ionizing radiation (IR) is widely used as a therapeutic option for many cancer types, but surviving cancer cells often acquire resistance after radiotherapy.[1]
IR-Induced Bcl-w Promotes Mesenchymal Traits, Migratory and Angiogenic Potentials, and Stemness Maintenance To determine whether Bcl-w contributes to the acquisition of IRinduced aggressive properties in cancer cells, we evaluated its effects on IR-mediated tumorigenicity, including mesenchymal-related traits, migration, angiogenesis, and maintenance of stemness
Based on H&E staining and graphical presentation of the lung nodule number, decreased pulmonary metastasis was detected in IR-treated mice in the presence of miR-205-5p compared to IR-only-exposed mice (Figure 5G). In view of these findings, we propose that miR-205-5p may be effectively used as a target for genetic therapy aimed at inhibiting IR-induced resistance events, such as malignant activity and metastasis
Summary
Ionizing radiation (IR) is widely used as a therapeutic option for many cancer types, but surviving cancer cells often acquire resistance after radiotherapy.[1]. Bcl-w (B cell lymphoma-w) is upregulated in gastric, colorectal, breast, cervical, lung, and bladder cancers, and glioblastoma multiforme[12,13,14,15,16,17,18,19,20] and acts as a potential mediator of resistance to several chemotherapeutic drugs owing to its activity in preventing cell death[21] as a pro-survival factor. Bcl-w promotes tumor progression and stemness in gastric cancer cells and glioblastoma multiforme[15,17,22] as a pro-oncogene.[23] the relationship between IR-induced resistance and Bcl-w expression in cancers is currently unclear
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