CCAT2 knockdown inhibits cell growth, and migration and promotes apoptosis through regulating the hsa-mir-145-5p/AKT3/mTOR axis in tamoxifen-resistant MCF7 cells.

AIMS: Tamoxifen (TAM) selectively modulates estrogen receptors and is widely used in breast cancer treatment. However, resistance to this drug appears in 40 % of estrogen receptor-positive breast cancer patients due to deregulated non-coding RNAs. This study sought to identify a long non-coding-RNA/miRNA/mRNA axis that is involved in the development of resistance to TAM- in MCF7 cells (MCF7-R). MAIN METHODS: Study genes were selected using RNA-seq. The expression of genes was assessed using TCGA cohort analyses and RT-qPCR. To identify potential resistant pathways in MCF7-R, the DAVID and DIANA-miRPath were carried out. The prediction software (RNAhybrid, TargetScan, and LncTar), and RT-qPCR were used to determine the relationship between genes. Next, the MCF7-R was established and RT-qPCR, cell cycle, apoptosis, and wound healing assays were carried out to verify MCF7-R and identify the effects of CCAT2 overexpression and knockdown on the cells. KEY FINDINGS: Based on bioinformatics analyses, CCAT2, AKT3, and mTOR were up-regulated in breast cancer cell lines, tissues, and TAM-resistant cells, while hsa-miR-145-5p was down-regulated. According to DAVID and DIANA-miRPath, PI3K/AKT/mTOR was a pathway involved in MCF7-R. According to the prediction software, and RT-qPCR results, CCAT2/hsa-miR-145-5p and hsa-miR-145-5p/AKT3 had a negative correlation. CCAT2 knockdown could prevent cell growth, and migration, and promote apoptosis in MCF7-R, while CCAT2 overexpression induced the opposite effects. RT-qPCR revealed that the expression of BAX and Bcl-2 genes were regulated in favor of apoptosis, upon CCAT2 knockdown. SIGNIFICANCE: CCAT2 regulates cell cycle, migration, and apoptosis in MCF7-R via the hsa-miR-145-5p/AKT3/mTOR axis. Therefore, CCAT2 may be a target to enhance the sensitivity of resistant MCF7 cells to TAM.

Signaling pathways involved in chronic myeloid leukemia pathogenesis: The importance of targeting Musashi2-Numb signaling to eradicate leukemia stem cells.

OBJECTIVES: Chronic myeloid leukemia (CML) is a myeloid clonal proliferation disease defining by the presence of the Philadelphia chromosome that shows the movement of BCR-ABL1. In this study, the critical role of the Musashi2-Numb axis in determining cell fate and relationship of the axis to important signaling pathways such as Hedgehog and Notch that are essential for self-renewal pathways in CML stem cells will be reviewed meticulously. MATERIALS AND METHODS: In this review, a PubMed search using the keywords of Leukemia, signaling pathways, Musashi2-Numb was performed, and then we summarized different research works . RESULTS: Although tyrosine kinase inhibitors such as Imatinib significantly kill and remove the cell with BCR-ABL1 translocation, they are unable to target BCR-ABL1 leukemia stem cells. The main problem is stem cells resistance to Imatinib therapy. Therefore, the identification and control of downstream molecules/ signaling route of the BCR-ABL1 that are involved in the survival and self-renewal of leukemia stem cells can be an effective treatment strategy to eliminate leukemia stem cells, which supposed to be cured by Musashi2-Numb signaling pathway. CONCLUSION: The control of molecules /pathways downstream of the BCR-ABL1 and targeting Musashi2-Numb can be an effective therapeutic strategy for treatment of chronic leukemia stem cells. While Musashi2 is a poor prognostic marker in leukemia, in treatment and strategy, it has significant diagnostic value.