Our study aimed to investigate the effects of lncRNA LOXL1-AS1/miR-let-7a-5p/EGFR-axis on prostate cancer (PCa) progression. Microarray analysis was conducted to determine differentially expressed lncRNAs and mRNAs. Gene Set Enrichment analysis was implemented for verification of dys-regulated signaling pathways between DU-145 cells and doxorubicin-resistant prostate cancer DU-145 cells. Relative expression of lncRNA LOXL1-AS1 in doxorubicin-resistant prostate cancer DU-145 cells was analyzed by qRT-PCR. CCK-8 assay and flow cytometry analysis were employed to detect cell proliferation and apoptosis, respectively. Cell migration was performed by transwell assay. Furthermore, targeted relationships between lncRNA LOXL1-AS1 and miR-let-7a-5p, as well as miR-let-7a-5p and EGFR were predicted using bioinformatics analysis and validated by dual-luciferase reporter gene assay. Besides, tumor xenograft assay was utilized for verification of the roles of LOXL1-AS1 in PCa progression in vivo. Microarray analysis showed that lncRNA LOXL1-AS1 and EGFR were both downregulated, while miR-let-7a-5p was upregulated in doxorubicin-resistant prostate cancer DU-145 cells. MiR-let-7a-5p could target both lncRNA LOXL1-AS1 and EGFR to affect PCa progression. Upregulation of lncRNA LOXL1-AS1 promoted cell proliferation and migration, while suppressed cell apoptosis. Besides, it was further confirmed that EGFR was downregulated in drug-resistant PCa cells and negatively correlated with miR-let-7a-5p. Tumor xenograft assay verified that silence of lncRNA LOXL1-AS1 inhibited the tumor growth in vivo in DU-145 cells. Our results demonstrated that the lncRNALOXL1-AS1/miR-let-7a-5p/EGFR axis significantly affected proliferation, migration, and apoptosis of drug-resistant DU-145 Cells, which may provide us with a potential treatment strategy for drug-resistant PCa patients. (c) 2019 IUBMB Life, 2019