Abstract
BackgroundCell autophagy has been proposed to be involved in drug resistance therapy. However, how the long non-coding RNA (lncRNA) reduces risks of drug resistance in renal cancer (RC) cells needs a thorough inquiry. This study was assigned to probe the effect and mechanism of HOTAIR on sunitinib resistance of RC.MethodsClinical RC tissues and para-carcinoma tissues were obtained to detect the expressions of miR-17-5p, HOTAIR and Beclin1. Sunitinib-resistant cells (786-O-R and ACHN-R) were constructed using parental RC cells (786-O and ACHN). The resistance of 786-O-R and ACHN-R cells to sunitinib was examined. Western blot and qRT-PCR were assayed to obtain the expressions of miR-17-5p, HOTAIR and Beclin1. The effects of HOTAIR knockdown or miR-17-5p overexpression/knockdown on cell autophagy and sunitinib resistance were measured by MDC staining, immunofluorescence and Western blot. The sensitivity of RC cells to sunitinib and change in cell clone formation after sunitinib treatment were assessed by CCK-8 assay and colony formation assay, respectively. The relationships among HOTAIR, miR-17-5p and Beclin1 were verified by dual-luciferase reporter gene and RIP assay. The role of HOTAIR knockdown in sunitinib resistance was verified in nude mice.ResultsHOTAIR expression in sunitinib-resistant cells is higher than that in parental cells. Knockdown of HOTAIR in sunitinib-resistant cells lead to refrained sunitinib resistance and cell autophagy both in vivo and in vitro. Activation of autophagy could raise resistance to sunitinib in RC cells, while inhibition of autophagy could improve the sensitivity of sunitinib-resistant cells to sunitinib. HOTAIR could compete with miR-17-5p to regulate Beclin1 expression. Knockdown of miR-17-5p in parental cells increases cell resistant to sunitinib, and overexpression of miR-17-5p in sunitinib-resistant cells increases cell sensitive to sunitinib.ConclusionHOTAIR negatively targets miR-17-5p to activate Beclin1-mediated cell autophagy, thereby enhancing sunitinib resistance in RC cells.
Highlights
Cell autophagy has been proposed to be involved in drug resistance therapy
We found that sunitinib treatment had no effect on tumor size of mouse received thirdgeneration xenograft (Fig. 1a), presenting the xenograft exhibited sunitinib resistance
Knockdown of Long non-coding RNA (LncRNA) HOX transcript antisense intergenic RNA (HOTAIR) inhibits autophagy and sunitinib resistance in renal cancer (RC) cells The expressions of HOTAIR, miR-17-5p and Beclin1 in RC tissues and para-carcinoma tissues were analyzed by Quantitative reverse transcription polymerase chain reaction (qRT-PCR)
Summary
Cell autophagy has been proposed to be involved in drug resistance therapy. How the long non-coding RNA (lncRNA) reduces risks of drug resistance in renal cancer (RC) cells needs a thorough inquiry. This study was assigned to probe the effect and mechanism of HOTAIR on sunitinib resistance of RC. Li et al Cancer Cell Int (2020) 20:338 metastatic RC is about 30%, whereas less than 10% of patients had a survival period longer than 5 years [2]. Autophagy regulation has been reported to reverse the resistance to chemotherapy [6]. Inhibition of autophagic flux and sequestration in lysosomes were proved to result in resistance to sunitinib in renal cell carcinoma [8]. Much still remains to be elucidated for autophagy regulation on sunitinib chemosensitivity in RC cells
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