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Background: It is reported that progestin and adipoQ receptor 4 (PAQR4) has a tumorigenic effect on human breast cancer, but the role of PAQR4 in non-small-cell lung cancer (NSCLC) is unknown. The aim of this study was to investigate the role of PAQR4 in NSCLC. Methods: Quantitative real-time PCR (qRT-PCR) and immunohistchemical (IHC) staining were used to analyze the expression of PAQR4 in HCC tissues and adjacent normal tissues. MTT, colony formation assay, flow cytometry (FCM), wound healing assays and transwell invasion assays were used to investigate the effects of PAQR4 on cell proliferation, colony formation, cell cycle, migration and invasion. Murine xenograft model assay was carried out to characterize the effects of PAQR4 knockdown on tumor growth in vivo. Results: In this study, we found that the expression of PAQR4 was significantly upregulated in the NSCLC tissues of patients compared with that in the matched non-cancerous tissues. In addition, we found that PAQR4 was also significantly up-regulated in the NSCLC cell lines compared with normal human lung epithelial cells. Besides, we found that the over-expression of PAQR4 promoted promoted proliferation, colony formation, migration and invasion of the NSCLC cells, whereas the knockdown of PAQR4 inhibited proliferation, colony formation, migration and invasion of the NSCLC cells. Furthermore, mechanistic studies showed that the CDK4-pRB-E2F1 pathway was involved in NSCLC. Conclusion: Hence, these results suggest that PAQR4 may be used as a new target in NSCLC therapy. [ABSTRACT FROM AUTHOR]