P65‐mediated miR‐590 inhibition modulates the chemoresistance of osteosarcoma to doxorubicin through targeting wild‐type p53‐induced phosphatase 1

• Published in: Journal of cellular biochemistry Vol. 120; no. 4; pp. 5652 - 5665
• Main Authors: Long, Xiao, Lin, Xiang‐Jin
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.04.2019
• Subjects: Apoptosis; Ataxia; ataxia telangiectasia mutated (ATM)‐p53 signaling; Ataxia telangiectasia mutated protein; Biocompatibility; Biotechnology; Bone cancer; Bone tumors; Cancer; Cell proliferation; Chemoresistance; Deoxyribonucleic acid; DNA; DNA damage; Doxorubicin; Gene expression; Inhibition; miRNA; miR‐590; Morbidity; Osteosarcoma; osteosarcoma (OS); p53 Protein; p65; Phosphatase; Radiation; Radiation tolerance; RelA protein; Sarcoma; Sensitizing; Signal transduction; Signaling; Tissues; wild‐type p53‐induced phosphatase 1 (WIP1); miR-590; chemoresistance; osteosarcoma (OS); ataxia telangiectasia mutated (ATM)-p53 signaling; p65; wild-type p53-induced phosphatase 1 (WIP1)
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.27849

Osteosarcoma (OS) is a primary malignant bone tumor with high morbidity. Developing new therapeutic approaches with neoadjuvant is of great interest in OS treatment. Reportedly, ataxia telangiectasia mutated (ATM)/ataxia telangiectasia and radiation resistance gene 3 related (ATR)‐p53 signaling is considered as a critical DNA damage signaling pathway sensitizing cancer cells to chemotherapies; while wild‐type p53‐induced phosphatase 1 (WIP1), an oncogene overexpressed in diverse cancers, has been regarded as a critical inhibitor in the ATM/ATR‐p53 DNA damage signaling pathway. Herein, the expression of WIP1 in OS tissues and cell lines was examined; to investigate the mechanism of WIP1 abnormal upregulation, online tools were used to predict the upstream regulatory microRNAs (miRNAs) targeting WIP1. Among the candidate miRNAs, the expression and detailed function of miR‐590 were validated. Through binding to the 3′‐untranslated region of WIP1, miR‐590 inhibited WIP1 expression and, therefore, enhanced the effect of Dox on OS cell proliferation and apoptosis through downstream ATM‐p53 signaling. Moreover, RELA could bind to the promoter region of miR‐590 to inhibit its expression, thereby affecting downstream WIP1 and ATM‐p53 signaling. The expression of p65 was upregulated in OS tissues, indicating that the effect of p65 inhibition on cell viability, apoptosis, and related mechanisms could be partially restored by miR‐590 inhibition. Taken together, these results showed that p65‐mediated miR‐590/WIP1/ATM‐p53 modulation might be a novel target to enhance the cellular effect of Dox on OS cell lines. Understanding the mechanism of the chemoresistance of osteosarcoma (OS) and developing new therapeutic approaches with neoadjuvant are of great interest in OS treatment. Herein, we demonstrate that p65 binds to the promoter region of miR‐590 to inhibit its expression, thereby affecting the cellular effect of Dox on OS cell lines through downstream wild‐type p53‐induced phosphatase 1 (WIP1) and ataxia telangiectasia mutated (ATM)‐p53 signaling.