1. A long noncoding RNA critically regulates Bcr-Abl-mediated cellular transformation by acting as a competitive endogenous RNA
- Author
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Guijie Guo, Tan H, Lianfeng Zhang, Qinghuang Chen, Xiaogang Wang, Ji-Long Chen, Xueliang Zhu, Kang Q, Jianyong Ouyang, Shile Huang, Yuhai Chen, and Runsheng Chen
- Subjects
Cancer Research ,Transplantation, Heterologous ,Fusion Proteins, bcr-abl ,Mice, Nude ,Apoptosis ,Mice, Transgenic ,Piperazines ,Proto-Oncogene Proteins c-myc ,Jurkat Cells ,Mice ,Cell Line, Tumor ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,microRNA ,Genetics ,Animals ,Humans ,PTEN ,Tensin ,RNA, Messenger ,Protein Kinase Inhibitors ,Molecular Biology ,Oligonucleotide Array Sequence Analysis ,biology ,Gene Expression Regulation, Leukemic ,PTEN Phosphohydrolase ,RNA ,Hep G2 Cells ,DNA Methylation ,Molecular biology ,Long non-coding RNA ,Cell biology ,MicroRNAs ,Cell Transformation, Neoplastic ,HEK293 Cells ,Pyrimidines ,Benzamides ,DNA methylation ,Imatinib Mesylate ,MCF-7 Cells ,biology.protein ,RNA, Long Noncoding ,Ectopic expression ,K562 Cells ,Neoplasm Transplantation ,K562 cells - Abstract
Aberrant expression of long noncoding RNAs (lncRNAs) is associated with various human cancers. However, the role of lncRNAs in Bcr-Abl-mediated chronic myeloid leukemia (CML) is unknown. In this study, we performed a comprehensive analysis of lncRNAs in human CML cells using an lncRNA cDNA microarray and identified an lncRNA termed lncRNA-BGL3 that acted as a key regulator of Bcr-Abl-mediated cellular transformation. Notably, we observed that lncRNA-BGL3 was highly induced in response to disruption of Bcr-Abl expression or by inhibiting Bcr-Abl kinase activity in K562 cells and leukemic cells derived from CML patients. Ectopic expression of lncRNA-BGL3 sensitized leukemic cells to undergo apoptosis and inhibited Bcr-Abl-induced tumorigenesis. Furthermore, transgenic (TG) mice expressing lncRNA-BGL3 were generated. We found that TG expression of lncRNA-BGL3 alone in mice was sufficient to impair primary bone marrow transformation by Bcr-Abl. Interestingly, we identified that lncRNA-BGL3 was a target of miR-17, miR-93, miR-20a, miR-20b, miR-106a and miR-106b, microRNAs that repress mRNA of phosphatase and tensin homolog (PTEN). Further experiments demonstrated that lncRNA-BGL3 functioned as a competitive endogenous RNA for binding these microRNAs to cross-regulate PTEN expression. Additionally, our experiments have begun to address the mechanism of how lncRNA-BGL3 is regulated in the leukemic cells and showed that Bcr-Abl repressed lncRNA-BGL3 expression through c-Myc-dependent DNA methylation. Taken together, these results reveal that Bcr-Abl-mediated cellular transformation critically requires silence of tumor-suppressor lncRNA-BGL3 and suggest a potential strategy for the treatment of Bcr-Abl-positive leukemia.
- Published
- 2014