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  • br Results br Discussion Although they do not

    2023-01-26


    Results
    Discussion Although they do not have protein-coding capacity, lncRNAs make up a large part of the transcripts of the genome, and they play fundamental roles in carcinogenesis and osteosarcoma progression through regulation of tumor proliferation and metastasis. These lncRNAs include MALAT1 and TUG1 [26], [27]. However, there has been little research on the mechanism of lncRNA regulation on receptor tyrosine kinases. In the present study, we demonstrated that the novel lncRNA DANCR was dysregulated in osteosarcoma, and its expression was correlated with poor patient survival and was an independent predictor. Similarly, DANCR over-expression increased osteosarcoma cell proliferation, migration and invasion in vitro, whereas DANCR inhibition had the opposite effects. Ectopic DANCR expression also promoted xenograft tumor growth and lung metastasis in vivo. Consistent with the function of other lncRNAs [15], [16], [17], we demonstrated that DANCR expression was significantly correlated with stem cell gene expression in osteosarcoma tissues, including CD133, etc. In vitro, DANCR over-expression significantly increased CD133, SOX2, and CD90 expression in osteosarcoma cells. The percentage of CD133 and CD44 double positive SKF 83566 hydrobromide sale significantly increased upon stable DANCR over-expression, and DANCR expression was also increased in CD133 and CD44 double positive cells. Moreover, DANCR over-expression increased the number and size of stem-like osteosarcoma cell spheres. Taken together, we demonstrated that DANCR expression enhances tumorigenesis and progression by promoting CSCs in osteosarcoma. The molecular mechanisms of lncRNA must be elucidated, and localization is important for their function. lncRNAs enriched in the nucleus largely participate in transcriptional regulation as decoy elements and chromatin modifiers, and those in the cytoplasm typically participate in post-transcriptional regulation by interacting with microRNAs or mRNAs [28], [29]. In the present study, we showed that DANCR was primarily localized to the cytoplasm, indicating its post-transcriptional regulation of osteosarcoma cells. Axl is a member of the TAM (Tyro3, Axl, Mer) family of receptor tyrosine kinases, originally identified as a transforming gene in the cells of chronic myelogenous leukemia patients [30]. Axl regulates tumor cell self-renewal, EMT and chemoresistance [31]. Similarly, we demonstrated that AXL promotes osteosarcoma progression by affecting p-AKT expression [24] and is down-regulated by miR-199a [32]. Therefore, it was interesting to determine whether there existed a regular network between DANCR and AXL. Interestingly, in the present study, although DANCR did not directly bind to AXL mRNA, both had the same putative binding sequences with miR-33a-5p. Moreover, there were correlations among DANCR, AXL, and miR-33a-5p both in osteosarcoma cell line and tumor tissues. We also demonstrated that DANCR over-expression was positively correlated with AXL mRNA and negatively related to miR-33a-5p, which strongly indicates a regulatory net work among the three factors in osteosarcoma cells. Our results also suggest that DANCR is a crucial upregulator of osteosarcoma and an independent predictor of prognosis. Our hypothesis was similar to that of TGF-beta activation of lncRNA in HCC invasion and metastasis via the upregulation of ZEB1 and ZEB2 through competitive binding to the miR-200 family and activation of the STAT3 signaling pathway [33]. We also suggest that DANCR upregulates AXL mRNA and protein expression and affects the expression of other proteins downstream of Axl in the PI3K-Akt pathway. This signaling pathway also regulates self-renewal, colony formation, EMT, and aldehyde dehydrogenase 1 (ALDH1) activity of tumor CSCs [34].
    Statements of author contributions
    Acknowledgements This work was supported by the National Natural Science Foundation of China (NSFC) (Grant No.81302348). The manuscript was polished by Elsevier Language Editing.