Abstract
Radiotherapy in osteosarcoma patients is problematic due to radioresistance; therefore, understanding the mechanism of radioresistance is integral to providing effective radiotherapeutic regimens for osteosarcoma. We now report the activity of an miRNA, miR-513a-5p, in stimulating radiosensitivity of osteosarcoma cells in vitro and in vivo. MiR-513a-5p expression is decreased in osteosarcoma tissue from patients and cultured osteosarcoma cell lines. However, exogenous re-expression of this miRNA in osteosarcoma cell lines, including HOS, U2OS and 9901, can induce sensitization to ionizing radiation. We also confirm that miR-513a-5p suppresses APE1 expression, and that both the redox and DNA repair activity of APE1 were decreased in miR-513a-5p expressing cell lines. By suppressing APE1, miR-513a-5p induces the DNA damage response which stimulates apoptosis after irradiation. Our report establishes miR-513a-5p as a radiosensitizing miRNA and identifies its activity in the suppression of APE1, which could directly lead to radiosensitization.
Highlights
Osteosarcoma is the most common histological type of primary bone malignancy and is most prevalent in children and adolescents
We initially detected the expression of miR-513a5p using quantitative PCR in formalin fixed paraffin embedded (FFPE) tissue from both osteosarcoma patients and healthy donors
Reduced expression of miR-513a-5p is observed in bone tissue from both osteosarcoma patients and healthy donors compared to other miRNAs which have been reported to be highly expressed in osteosarcoma, such as let-7a or miR-451(20)
Summary
Osteosarcoma is the most common histological type of primary bone malignancy and is most prevalent in children and adolescents. While radiotherapy is a powerful therapeutic strategy for solid tumors, its use in osteosarcoma is controversial because of radioresistance [2, 3]. Ionizing radiation (IR), the major form of irradiation used in radiotherapy, causes oxidative DNA base damage by stimulating reactive oxygen species (ROS) through hydrolysis. APE1 is highly expressed (reviewed in [6]) and is associated with radioresistance in various types of cancers, including osteosarcoma, according to previous studies by our group and others [7,8,9,10,11,12,13,14,15]. This study indicated that the DNA repair activity, which is evolutionarily conserved, is required for cell survival after www.oncotarget.com
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