Knockdown of miR-15b partially reverses the cisplatin resistance of NSCLC through the GSK-3β/MCL-1 pathway

Abstract

Background. Induction of acquired drug resistance occurs frequently with cisplatin-based therapy for non-small cell lung cancer (NSCLC). As recent studies have demonstrated that deregulation of microRNAs (miRNAs) is associated with drug resistance in cancers, correcting the deregulation of miRNAs represents a promising strategy to reverse acquired resistance in NSCLC.Objectives. This study investigated the functional role of miR-15b in cisplatin resistance in NSCLC. Materials and methods.Cisplatin-resistant PC9 and A549 NSCLC cell lines (PC9-R and A549-R) were established through long-term exposure to cisplatin. Differences in miR-15b expression between cisplatin-resistant NSCLC cell lines and their parental cell lines were identified through quantitative real-time polymerase chain reaction (qRT-PCR). The effect of anti-miR-15b on the sensitivity of PC9-R and A549-R to cisplatin-induced cytotoxicity was evaluated using Cell Counting Kit-8 (CCK-8) assays. Regulation of GSK-3β by miR-15b was confirmed with luciferase reporter assays. Cell apoptosis and mitochondrial membrane potential (MMP) were measured using flow cytometry analysis.Results. In PC9-R and A549-R cells, miR-15b was significantly overexpressed. However, knockdown of miR-15b clearly reduced cisplatin resistance in PC9-R and A549-R cells. Researching the mechanism, we proved that GSK-3β was the target of miR-15b. Knockdown of miR-15b significantly increased the expression GSK-3β and thus promoted the degradation of MCL-1, which is a key anti-apoptosis protein. As a result, anti-miR-15b expanded the cisplatin-induced apoptosis in cisplatin-resistant NSCLC cells.Conclusions. Knockdown of miR-15b partially reversed cisplatin resistance in NSCLC cells through the GSK-3β/MCL-1 pathway.

The Role of the Selected miRNAs as Diagnostic, Predictive and Prognostic Markers in Non-Small-Cell Lung Cancer

“…MiR-15 was identified as an oncomir in various cancer types, including the NSCLC [ 47 ]. MiR-15b overexpression has been linked to cisplatin resistance.…”

“…MiR-15b overexpression has been linked to cisplatin resistance. Anti-miR-15b notably restored cisplatin sensitivity in NSCLC cells [ 47 ] ( Table 2 ). The miR-15-16 cluster’s expression was limited by hypoxia, which supported tumour angiogenesis and metastasis [ 40 ].…”

“…Regulating the miR-129-2 levels, on the other hand, could be a way to enhance the chemotherapy’s effectiveness [ 81 ]. The overexpression of the following miRNAs was shown to contribute to the cisplatin-resistance of the NSCLC cells: miR-15 [ 47 ], miR-25 [ 46 ], mir-26a [ 48 , 49 ], miR-31 [ 28 ], miR-494 [ 52 ], mir-556-5p [ 53 ], miR-4443 [ 54 ]. On the other hand, the increased expression of the miR-126-5p [ 50 ], miR-146a [ 25 ] and mir-320 [ 51 ] improved the cells’ cisplatin sensitivity.…”

Engineered Exosomes-Mediated Transfer of hsa-miR-320a Overcomes Chemoresistance in Cervical Cancer Cells via Targeting MCL1

“…It was reported that MCL1 is a key molecule in cisplatin resistance, such as. MCL1 in non-small cell lung cancer (NSCLC) ( Ma et al, 2016 ; Lu et al, 2021 ) and hypopharyngeal squamous cell carcinoma ( Liu X. et al, 2021 ). The miR-320a/MCL1 axis mediates the doxorubicin resistance of osteosarcoma ( Zhou et al, 2018 ).…”

MicroRNAs as Predictors of Lung-Cancer Resistance and Sensitivity to Cisplatin

“…The following supporting information can be downloaded at: . References [ 25 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , ...…”