Circ_ZFR contributes to the paclitaxel resistance and progression of non-small cell lung cancer by upregulating KPNA4 through sponging miR-195-5p

Abstract

Background A growing body of evidence has demonstrated the vital roles of circular RNAs (circRNAs) in cancer progression and drug resistance. We intended to explore the roles and mechanisms of circ_ZFR in the paclitaxel (PTX) resistance and progression of non-small cell lung cancer (NSCLC). Methods Two NSCLC cell lines A549 and H460 were used in this study. Quantitative real-time polymerase chain reaction (qRT-PCR) assay was conducted to measure the levels of circ_ZFR, ZFR, miR-195-5p and karyopherin subunit alpha 4 (KPNA4) mRNA. RNase R assay was used to analyze the characteristic of circ_ZFR. MTT assay was carried out to assess PTX resistance and cell proliferation. Flow cytometry analysis was utilized to analyze cell cycle and apoptosis. Transwell assay was used to examine cell migration and invasion. Western blot assay was conducted to measure the protein levels of Ki67, Twist1, E-cadherin and KPNA4. Dual-luciferase reporter assay was adopted to verify the combination between miR-195-5p and circ_ZFR or KPNA4. Murine xenograft model assay was used to investigate the effect of circ_ZFR on PTX resistance of NSCLC in vivo. Results Circ_ZFR level was enhanced in PTX-resistant NSCLC tissues and cells. Knockdown of circ_ZFR suppressed PTX resistance, cell cycle process, proliferation, migration and invasion and induced apoptosis in PTX-resistant NSCLC cells. For mechanism analysis, circ_ZFR knockdown markedly downregulated the expression of KPNA4 by sponging miR-195-5p, thereby promoting PTX sensitivity and suppressing cell progression in PTX-resistant NSCLC cells. In addition, circ_ZFR silencing enhanced PTX sensitivity of NSCLC in vivo. Conclusion Circ_ZFR knockdown played a positive role in overcoming PTX resistance of NSCLC via regulating miR-195-5p/KPNA4 axis, which might provide a possible circRNA-targeted therapy for NSCLC.

Circ_0061140 knockdown inhibits tumorigenesis and improves PTX sensitivity by regulating miR-136/CBX2 axis in ovarian cancer

“…Circ_BIRC6 overexpression relieved PTX-induced repression of hepatocellular carcinoma progression through trapping miR-877-5p [ 29 ]. Additionally, circ_ZFR promoted PTX resistance in lung cancer in a miR-195-5p-dependent manner [ 30 ]. Circ_0061140 has been identified as a tumor promoter in bladder cancer [ 31 ], endometrial carcinoma [ 32 ] and prostate cancer [ 33 ].…”

Construction of a circRNA-Related Prognostic Risk Score Model for Predicting the Immune Landscape of Lung Adenocarcinoma

“…An increasing amount of evidence has shown that circRNAs are involved in several physiological and pathological processes of tumor development and progression ( Song and Fu, 2019 ; Wang et al, 2019 ; Zhang et al, 2019a , b , c ; Bai et al, 2020 ; Zhang N. et al, 2020 ; Zhang S. J. et al, 2020 ). CircRNAs have also been shown to be involved in resistance to immunotherapy, targeted therapy, and chemotherapy ( Zhang et al, 2019b ; Wen et al, 2020 ; Li et al, 2021 ). In this study, we identified abnormal gene expression in LUAD with data from the GEO database.…”

Biogenesis, functions, and clinical implications of circular RNAs in non-small cell lung cancer

“… 82 circ_ZFR up miR-195-5p 64 NSCLC tissue samples; A549 and H460 NSCLC cell lines silencing circ_ZFR inhibits PTX resistance, cell-cycle process, proliferation, migration, and invasion and promotes apoptosis in PTX-resistant NSCLC cells by sponging miR-195-5p to upregulate KPNA4 expression Li et al. 83 circGFRA1 up miR-188-3p 30 NSCLC tissue samples; A549 and H803 NSCLC cell lines upregulation of circGFRA1 promotes cancer cell proliferation by sponging miR-188-3p to activate the PI3K/AKT signaling pathway Yao et al. 84 hsa_circ_0014130 up miR-136-5p 30 NSCLC tissue samples; A549 and PC-9 NSCLC cell lines downregulation of hsa_circ_0014130 suppresses NSCLC progression by sponging miR-136-5p to increase Bcl-2 expression Geng et al.…”

“…The knockdown of circ_ZFR inhibits the taxol resistance of NSCLC by sponging miR-195-5p to decrease KPNA4 expression. 83 Some circRNAs, such as circ_0007385 and circ-PRMT5, are reported to be involved in the regulation of the DDP resistance of NSCLC cells. circ_0007385 knockdown has been shown to repress the DDP resistance of NSCLC cells.…”