Abstract
Cisplatin resistance is a major obstacle in the treatment of NSCLC, and its mechanism has not been fully elucidated. The objectives of the study were to determine the role of miR-378 in the sensitivity of lung adenocarcinoma cells to cisplatin (cDDP) and its working mechanism. With TargetScan and luciferase assay, miR-378 was found to directly target sCLU. miR-378 and sCLU were regulated in A549/cDDP and Anip973/cDDP cells to investigate the effect of miR-378 on the sensitivity and apoptotic effects of cDDP. The effect of miR-378 upregulation on tumor growth was analyzed in a nude mouse xenograft model. The correlation between miR-378 and chemoresistance was tested in patient samples. We found that upregulation of miR-378 in A549/cDDP and Anip973/cDDP cells significantly down-regulated sCLU expression, and sensitized these cells to cDDP. miR-378 overexpression inhibited tumor growth and sCLU expression in a xenograft animal model. Analysis of human lung adenocarcinoma tissues revealed that the cDDP sensitive group expressed higher levels of miR-378 and lower levels of sCLU. miR-378 and sCLU were negatively correlated. To conclude, we identified sCLU as a novel miR-378 target, and we showed that targeting sCLU via miR-378 may help disable the chemoresistance against cisplatin in lung adenocarcinoma cells.
Highlights
Clusterin (CLU) is a secreted glycoprotein which is involved in many physiological processes, such as apoptosis, cell cycle regulation, and DNA repair[5,6,7]
The lower panel is the miR-378 sequence containing the putative sCLU binding site and its mutant sequence. (B) Dual luciferase assay was performed with co-transfection of miR-378 mimics and the reporter containing sCLU 3′ -untranslated region (UTR) wild-type versus mutant. (C) RT-PCR results showed that A549 cells had higher expression of miR-378 compared with A549/cDDP cells
The A549/cDDP cell line had a lower level of miR-378 and a higher level of sCLU compared with the A549 cell line (Fig. 1C,D)
Summary
Clusterin (CLU) is a secreted glycoprotein which is involved in many physiological processes, such as apoptosis, cell cycle regulation, and DNA repair[5,6,7] It has two main isoforms: secreted form (sCLU) and nuclear form (nCLU). We demonstrated that miR-378 targets sCLU, and explored its possible roles in chemoresistance to cDDP in lung adenocarcinoma cells. Lu discovered that 34 miRNAs were differentially expressed between the A549 and A549/cDDP cell line[16] Both reports demonstrated that miR-378 might be important in the chemoresistance to platinum, but the mechanisms for the effect remain poorly understood. We demonstrate that miRNA-378 regulates sCLU-mediated chemosensitivity to cDDP in non-small cell lung cancer cells
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