Abstract
MicroRNAs (miRNAs) have been identified as negative posttranscriptional regulators of target genes and are involved directly in the pathological processes of tumors, including drug resistance. However, the exact function of miR-520h in breast cancer remains poorly understood. The aim of this study was to investigate the molecular mechanisms of miR-520h in paclitaxel resistance in the MCF-7 breast cancer cell line. Ectopic expression of miR-520h could promote the proliferation of breast cancer cells and inhibit paclitaxel-induced cell apoptosis. Inhibiting the expression of miR-520h could enhance the sensitivity to paclitaxel in paclitaxel-resistant MCF-7/Taxol cells. Furthermore, luciferase reporter assays showed that OTUD3 was a direct target of miR-520h. OTUD3 plays a necessary role in the paclitaxel resistance effect of miR-520h, and cotreatment with a miR-520h inhibitor and OTUD3 overexpression significantly enhanced MCF-7 cell sensitivity to paclitaxel. Moreover, miR-520h substantially inhibited the protein expression of PTEN via OTUD3 and subsequently affected downstream p-AKT pathway activity. In a clinical study, we also found that high miR-520h expression was associated with more aggressive pathological characteristic and poor prognosis. Therefore, our findings showed that miR-520h targeted the OTUD3-PTEN axis to drive paclitaxel resistance, and this miR might be an important potential target for breast cancer treatment.
Highlights
Breast cancer is one of the most common invasive malignancies in women worldwide [1]
Despite advanced therapy strategies and improved early surveillance of breast cancer, drug resistance remains an important reason for systematic treatment failure [4]
The mechanisms responsible for drug resistance have been elucidated in multiple studies, and increasing evidence has demonstrated that miRNAs contribute to therapeutic resistance in cancers [14,15,16]
Summary
Breast cancer is one of the most common invasive malignancies in women worldwide [1]. Despite the development of various breast cancer treatment strategies, this disease still ranks second among the most common causes of cancer death in women [2]. Drug resistance strongly limits its efficacy and can cause systemic treatment failure [4]. Over the past few years, miRNAs have been shown to be involved in tumorigenesis, metastasis, and tumor response to treatment [7,8,9]. Many miRNAs have been reported to play critical roles in breast cancer progression [10, 11]. Previous studies showed that miR-520h acts as an oncogenic miRNA, and its downregulation by E1A is critical for E1A-mediated tumor and invasion suppression [12]
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