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Long noncoding RNA lncARSR confers resistance to Adriamycin and promotes osteosarcoma progression.

ABSTRACT: One of the significant challenges for chemotherapy is the appearance of resistance to compounds. Although several signaling pathways have been implicated in the development of Adriamycin (ADM) resistance, mechanisms involved in ADM-resistant osteosarcoma progression remain unknown. The present study attempted to illustrate the role of long noncoding RNA ARSR (lncARSR) in the development of adapted ADM resistance. We found lncARSR overexpressed in the Adriamycin-resistant cell lines U2OS/ADM and MG63/ADM, accompanied with acquired multidrug resistance against to paclitaxel and cisplatin. Overexpression of lncARSR triggered rhodamine 123 efflux and survival, as well as the migration of Adriamycin-resistant cells. Inversely, the depletion of lncARSR promoted rhodamine 123 retention and apoptosis, while reducing the motility of ADM-resistant cells. Further investigation revealed that the upregulation of lncARSR enhanced multidrug resistance-associated protein-1 (MRP1), apoptosis inhibitor Survivin, and matrix metalloproteinase-2 (MMP2) through activating AKT. The reduction of lncARSR overcame the resistance to ADM in U2OS/ADM mouse model. The current study gained novel evidence for understanding the mechanisms underlying adaptive ADM resistance and provided rationales to improve clinical outcomes of refractory osteosarcoma.

SUBMITTER: Shen P

PROVIDER: S-EPMC7220921 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundLong noncoding RNAs (lncRNAs) have critical regulatory functions in biological and pathological activities during osteosarcoma progression. It is important to elucidate the expression pattern and reveal the underlying mechanisms of the newly identified lncRNAs.MethodsHerein, we screened the differentially expressed lncRNAs in osteosarcoma tumors and cell lines using lncRNA microarray. The candidate lncRNA was further verified by qRT-PCR, and the association of gene expression with clinicopathological features was evaluated by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The targeting miRNA was identified using starBase analysis, and the competing endogenous RNA (ceRNA) network was established by STRING. Overexpression and silence of RNA were detected by qRT-PCR. Osteosarcoma cell proliferation was measured with CCK-8 assay, and the migration and invasion were evaluated with Transwell assay. Colony formation assay was observed. Flow cytometry evaluated the cell cycle. Western blot was performed to detect the mitotic markers and apoptosis-related proteins. A nude mouse tumor formation experiment was used to evaluate osteosarcoma progression in vivo. Cooverexpressing miR-34b-3p with RAD51 reversed the miR-34b-3p-induced changes in proliferation, the cell cycle, the expression of H2A.X, and that of apoptosis-related proteins.ResultsHCG9 was identified as osteosarcoma-associated lncRNA. Osteosarcoma tissues and cell lines expressed higher levels of HCG9 as compared to normal tissues and osteoblasts, and high expression of HCG9 was further proved to be related to metastasis and the grade of osteosarcoma in clinical cases. Knockdown of HCG9 inhibited the proliferation, migration, and invasion of osteosarcoma cells. miR-34b-3p was identified as the target of HCG9, and RAD51 acted as a potential target of miR-34b-3p. Cooverexpressing miR-34b-3p with HCG9 partially suppressed the HCG9-stimulated proliferation, migration, and invasion of osteosarcoma cells in vitro and delayed the tumor progression in vivo.ConclusionWe discovered that lncRNA HCG9 promoted the proliferation of osteosarcoma cells via suppressing miR-34b-3p. Our study provides novel biomarkers and potential therapeutic targets for osteosarcoma treatment.

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Long noncoding RNA lncARSR confers resistance to Adriamycin and promotes osteosarcoma progression.

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