Abstract
BackgroundOsteosarcoma is a common primary malignant bone cancer. Long noncoding RNA small nucleolar RNA host gene 15 (SNHG15) has been reported to play an oncogenic role in many cancers. Nevertheless, the role of SNHG15 in the doxorubicin (DXR) resistance of osteosarcoma cells has not been fully addressed.MethodsCell Counting Kit-8 assay was conducted to measure the half-maximal inhibitory concentration value of DXR in osteosarcoma cells. Western blotting was carried out to examine the levels of autophagy-related proteins and GDNF family receptor alpha-1 (GFRA1). Quantitative reverse transcription-polymerase chain reaction was performed to determine the levels of SNHG15, miR-381-3p, and GFRA1. The proliferation of osteosarcoma cells was measured by MTT assay. The binding sites between miR-381-3p and SNHG15 or GFRA1 were predicted by Starbase bioinformatics software, and the interaction was confirmed by dual-luciferase reporter assay. Murine xenograft model was established to validate the function of SNHG15 in vivo.ResultsAutophagy inhibitor 3-methyladenine sensitized DXR-resistant osteosarcoma cell lines to DXR. SNHG15 was upregulated in DXR-resistant osteosarcoma tissues and cell lines. SNHG15 knockdown inhibited the proliferation, DXR resistance, and autophagy of osteosarcoma cells. MiR-381-3p was a direct target of SNHG15, and GFRA1 bound to miR-381-3p in osteosarcoma cells. SNHG15 contributed to DXR resistance through the miR-381-3p/GFRA1 axis in vitro. SNHG15 depletion contributed to the inhibitory effect of DXR on osteosarcoma tumor growth through the miR-381-3p/GFRA1 axis in vivo.ConclusionsSNHG15 enhanced the DXR resistance of osteosarcoma cells through elevating the autophagy via targeting the miR-381-3p/GFRA1 axis. Restoration of miR-381-3p expression might be an underlying therapeutic strategy to overcome the DXR resistance of osteosarcoma.
Highlights
Osteosarcoma is the most common malignant bone cancer that mostly arises in childhood and adolescence [1]
These findings suggested that DXR resistance was associated with autophagy in osteosarcoma cells
(U2OS/DXR and MG63/DXR), and the autophagy inhibitor 3-MA sensitized DXR-resistant subclones to DXR, suggesting that the chemoresistance to DXR of osteosarcoma cells was associated with autophagy
Summary
Osteosarcoma is the most common malignant bone cancer that mostly arises in childhood and adolescence [1]. Liu et al reported that SNHG15 promoted growth, metastasis, and autophagy of osteosarcoma cells through negatively regulating miR-141 [15]. MiRNAs are another class of ncRNAs. MiRNAs can bind to the 3′-untranslated region (3′-UTR) of target messenger RNAs (mRNAs) through their “seed” sequence to reduce the levels of target mRNAs. MiR-3813p has been reported to play a suppressive role in many malignancies, including colorectal cancer, ovarian cancer, and renal cancer [16,17,18]. We investigated the role of GFRA1 in DXR-induced chemoresistance of osteosarcoma cells. We initially evaluated the role of lncRNA SNHG15 in DXR-induced chemoresistance of osteosarcoma cells, and the mechanism by which SNHG15 contributed to DXR resistance in osteosarcoma was explored. Institutional policies and in accordance with the tenets of the Helsinki Declaration, and has been approved by the Ethic Committee of Jingzhou Central Hospital, Second Clinical College of Yangtze University
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