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Long non-coding RNAs (lncRNAs) are emerging as an integral functional component of human genome and have been investigated as critical regulators in molecular biology of cancer. A recent study reported that lncRNA-UCA1 induced drug resistance in adriamycin chemotherapy. However, the contributions of lncRNAs to adriamycin resistance in cancers remain largely unknown. To address this issue, we performed a genome-wide lncRNA microarray analysis in adriamycin resistant MCF-7/ADR and parental MCF-7 cells, and revealed differential expression of lncRNAs in distinct category and chromosome distribution patterns. A specific differentially expressed lncRNA (Adriamycin Resistance Associated, termed ARA) was validated in MCF-7/ADR and HepG2/ADR cells. ARA is derived from an intron of PAK3 gene, predicted to contain several stable hairpins in secondary structure and has conservative sequences in primates. ARA expression is significantly associated with adriamycin sensitivity in a panel of breast and liver cancer cell lines and is markedly up-regulated in parental sensitive MCF-7 and HepG2 cell lines after receiving adriamycin treatment. The functions of ARA were assessed by silencing this lncRNA in vitro, and we found that ARA knockdown reduced the proliferation, induced cell death, G2/M arrest and migration defects. Furthermore, microarray transcriptomic analysis was carried out to comprehensively depict the ARA-regulated genes. We showed that ARA can modulate multiple signalling pathways, including MAPK signalling pathway, metabolism pathways, cell cycle and cell adhesion-related biological pathways, and regulate cellular processes, including transcriptional processes and protein binding function. Overall, our results indicate novel insights of adriamycin resistance in lncRNA level.