CircASXL1 Knockdown Restrains Hypoxia-Induced DDP Resistance and NSCLC Progression by Sponging miR-206

Abstract

Background Non-small cell lung carcinoma (NSCLC) is a primary prevalent type of cancer in people worldwide. Cisplatin (DDP) has been widely used to treat NSCLC; however, its curative effect was restrained under hypoxia. In this study, the effects of hypoxia treatment on DDP resistance and NSCLC progression and underneath mechanism were revealed. Methods The expression of circular RNA ASXL1 (circASXL1) and microRNA-206 (miR-206) in NSCLC tissues, cells and hypoxia-mediated NSCLC cells was determined by quantitative real-time polymerase chain reaction (qRT-PCR). The expression of proliferation, metastasis and apoptosis-related proteins, drug resistance-related protein and hypoxia-inducible factor-1alpha (HIF-1α) protein was detected by Western blot. The effects of circASXL1 knockdown on hypoxia-induced DDP resistance and NSCLC progression were revealed by cell counting kit-8 proliferation (CCK-8), cell colony formation, transwell and flow apoptosis assays. RNA immunoprecipitation (RIP) assay was performed to determine whether circASXL1 could form silence-inducing complexes with miRNA. The associated relationship between circASXL1 and miR-206 was predicted by circBank online database, and identified by RNA pull-down and dual-luciferase reporter assays. The effects between circASXL1 knockdown and miR-206 downregulation on tumor growth in vivo were investigated by in vivo tumor formation assay. Results CircASXL1 expression was dramatically upregulated, whereas miR-206 was significantly down-regulated in NSCLC tissues, cells and hypoxia-mediated NSCLC cells as compared to control groups. CircASXL1 knockdown reversed hypoxia-mediated promotion effects on DDP resistance, cell proliferation, migration, and invasion, and inhibition impact on cell apoptosis, whereas these effects were restored by miR-206 inhibitor. Additionally, circASXL1 was found to form silence-inducing complexes with miRNA and act as a sponge of miR-206. CircASXL1 silencing downregulated HIF-1α expression by controlling miR-206 expression. Furthermore, circASXL1 silencing repressed tumor growth in vivo by sponging miR-206. Conclusion CircASXL1 knockdown inhibited DDP resistance, cell proliferation, migration and invasion, whereas induced cell apoptosis under hypoxia by associating with miR-206 in NSCLC. This study provides a new sight in treating NSCLC with DDP under hypoxia.

RETRACTED ARTICLE: Circular RNA SOX13 promotes malignant behavior and cisplatin resistance in non-small cell lung cancer through targeting microRNA-3194-3p/microtubule-associated protein RP/EB family member 1

“…Additionally, miR-638 is available to inhibit NSCLC development via repressingFOSL2 expression [ 27 ]. Amid exploring the resistance mechanism, the researchers found that miR-139-5p [ 28 ], miR-1/133a, miR-206/133b cluster [ 29 ], and miR-221-3p23 promotes NSCLC sensitivity to chemical drugs which include cisplatin, gefitinib, osimertinib, paclitaxel and so on. Here, it was probed into the effect of miR-3194-3p on NSCLC malignant phenotype and cisplatin resistance, finding that miR-3194-3p is lowered in NSCLC, which restrainsNSCLC proliferation, migration and invasion but promotes its apoptosis.…”

The long and short non-coding RNAs modulating EZH2 signaling in cancer

“…The miRNA-26a has negative correlation with EZH2 in cytotoxic T cells and inhibits EZH2 signaling to disrupt T cell function and to enhance lung cancer progression [ 403 ]. An important feature of TME is hypoxia that can enhance both growth and metastasis of cancer cells [ 404 , 405 ]. The expression level of lncRNA HITT undergoes down-regulation in hypoxic TME that promotes progression of cervical and colorectal tumor cells.…”

Regulation of apoptosis, autophagy and ferroptosis by non‑coding RNAs in metastatic non‑small cell lung cancer (Review)

“…Knockdown of circ_0001821 may inhibit metastasis and paclitaxel resistance in NSCLC cells via the miR-526b-5p/GRK5 pathway ( 47 ). Furthermore, circASXL1 silencing can inhibit DDP resistance and tumorigenesis by sponging miR-206 in NSCLC tissues and cells ( 48 ). Interference with circ-PRMT5 has also been reported to induce apoptosis, reverse DDP resistance and reduce metastasis in DDP-resistant NSCLC.…”