MicroRNA-302 Replacement Therapy Sensitizes Breast Cancer Cells to Ionizing Radiation

Abstract

Purpose Solid tumors can be resistant or develop resistance to radiotherapy. The purpose of this study is to explore whether microRNA-302 is involved in radioresistance and can be exploited as a sensitizer to enhance sensitivity of breast cancer cells to radiation therapy. Methods MiR-302 expression levels in radioresistant cell lines were analyzed in comparison with their parent cell lines. Furthermore, we investigated whether enforced expression of miR-302 sensitized radioresistant breast cancer cells to ionizing radiation in vitro and in vivo. Results MiR-302 was downregulated in irradiated breast cancer cells. Additionally, the expression levels of miR-302a were inversely correlated with those of AKT1 and RAD52, two critical regulators of radioresistance. More promisingly, miR-302a sensitized radioresistant breast cancer cells to radiation therapy in vitro and in vivo and reduced the expression of AKT1 and RAD52. Conclusion Our findings demonstrated that decreased expression of miR-302 confers radioresistance and restoration of miR-302 baseline expression sensitizes breast cancer cells to radiotherapy. These data suggest that miR-302 is a potential sensitizer to radiotherapy.

microRNAs in Cancer Cell Response to Ionizing Radiation

“…In addition to PI3K, AKT is directly mediated by miRNA regulation, specifically the miR-302-367 cluster. Two groups simultaneously published evidence supporting this regulation, showing that miR-302 is responsible for repressing AKT expression with a single 3¢ UTR binding site (9,82). In addition, miR-302 is repressed in response to IR in breast cancer cells (82), perhaps as a mechanism to activate AKT and promote cell survival.…”

“…Two groups simultaneously published evidence supporting this regulation, showing that miR-302 is responsible for repressing AKT expression with a single 3¢ UTR binding site (9,82). In addition, miR-302 is repressed in response to IR in breast cancer cells (82), perhaps as a mechanism to activate AKT and promote cell survival. Despite having several poorly conserved putative miRNA binding sites in its 3¢ UTR, it is more likely that further AKT regulation occurs either directly or indirectly by other members of the PI3K/AKT pathway.…”

“…An over-expression of miR-210 and miR-373 in hypoxia forces the repression of RAD52, possibly reducing the efficiency of HR and promoting genomic instability in these hypoxic cells. On the other hand, over-expression of miR-302 is sufficient to sensitize cells to IR, presumably by down-regulating RAD52 and HR and promoting cell death (82). Interestingly, miR-302 is downregulated by IR (82,102,125), while there is no evidence supporting expression changes for miR-210 or miR-373 in response to IR.…”

“…In fact, it has been hypothesized that RAD52 plays a role in loading RAD51 onto the SS DNA in the absence of BRCA2, suggesting the possibility of redundant function (89). miRNA regulation of RAD52 has been demonstrated by miR-210, miR-302, and miR-373 (30,82). Crosby et al has shown that miR-210 and miR-373 are induced in hypoxia (30).…”

Ionizing Radiations Induce Apoptosis in TRAIL Resistant Cancer Cells: in vivo and in vitro Analysis

“…Breast cancer cells are mechanistically resistant to radiation and it is noteworthy that enforced expression of miR-302 in cancer cells resulted in an improved apoptotic response (Liang et al, 2013).…”