LncRNA SNHG15 contributes to doxorubicin resistance of osteosarcoma cells through targeting the miR-381-3p/GFRA1 axis

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.

Non-coding RNAs in drug and radiation resistance of bone and soft-tissue sarcoma: a systematic review

“…Of these, 43 investigated the molecular regulatory mechanisms of lncRNAs in chemotherapeutic drug resistance in OS, 101 focused on miRNAs, 21 on circRNAs, and one study reported on both lncRNA MEG3 and hsa_circ_0001258 ( Zhu et al, 2019 ). Moreover, 19 overlapping ncRNAs were reported in more than one study, including four lncRNAs (lncRNA SNHG15 [ Sun et al, 2022 ; Zhang et al, 2020a ], lncRNA OIP5-AS1 [ Song et al, 2019 ; Liu and Wang, 2020 ; Sun et al, 2020 ; Kun-Peng et al, 2019 ], lncRNA TUG1 [ Zhou et al, 2020 ; Hu et al, 2019 ], and lncRNA ANRIL [ Li and Zhu, 2019b ; Lee et al, 2021 ]), 13 miRNAs (miR-29b [ Luo et al, 2019 ; Li et al, 2020 ], miR-21 [ Vanas et al, 2016 ; Ziyan and Yang, 2016 ], miR-22 [ Wang et al, 2019c ; Li et al, 2014 ; Meng et al, 2020a ; Meng et al, 2020b ; Zhou et al, 2018b ], miR-199a-3p [ Lei et al, 2018 ; Gao et al, 2015 ], miR-34a-5p [ Pu et al, 2016 ; Pu et al, 2017b ; Pu et al, 2017a ], miR-34a [ Li et al, 2017 ; Novello et al, 2014 ; Chen et al, 2016a ], miR-140-5p [ Wei et al, 2016 ; Meng et al, 2017 ], miR-203 [ Chen et al, 2016a ; Huang et al, 2021 ], miR-19a-3p [ Zhang et al, 2019 ; Wang et al, 2022a ], miR-140 [ Song et al, 2009 ; Zhi et al, 2022 ], miR-29 [ Osaki et al, 2016 ; Xu et al, 2018b ], miR-221 [ Yu et al, 2019 ; Zhao et al, 2013 ], and miR-100 [ Xiao et al, 2017 ; Liu et al, 2016 ]), and two circRNAs (circPTV1 [ Li et al, 2021c ; Kun-Peng et al, 2018a ; Wang et al, 2022c ] and circRNA_0004674 [ Ma et al, 2021 ; Bai et al, 2021 ]) (…”

Tumor-associated macrophage-derived GDNF promotes gastric cancer liver metastasis via a GFRA1-modulated autophagy flux

“…Unfortunately, no reliable specific GFRA1 inhibitor is available, and we found that its classical co-receptor RET protein does not play a role in this process. Therefore, suitable drugs that can be used for clinical translation in patients with metastatic GC are currently lacking [ 44 – 46 ]. Thus, we further analysed the noncanonical mechanism driven by GFRA1 during GC liver metastasis and found that control over the autophagic activity of GC cells is a main mechanism [ 21 , 28 ].…”

Long noncoding RNA SNHG15: A promising target in human cancers

“…Likewise, SNHG15 suppressed cisplatin-induced apoptosis and ROS accumulation through the miR-335-3p/ZNF32 axis and was involved in p53-mediated cisplatin resistance in OS cells ( 58 ). Interestingly, SNHG15 might also target the miR-381-3p/GFRA1 axis to reduce apoptosis by inducing autophagy, leading to chemotherapy resistance to doxorubicin ( 55 ). Several findings above may provide new insights into the discovery of strategies for OS treatment.…”

“…Overall, SNHG15 was up-regulated in drug-resistant cancer tissues and cell lines ( 34 , 45 , 52 , 55 , 58 , 60 , 65 ). Several findings above may provide new insights into the discovery of strategies for treatment.…”