Bioinformatic analysis of the expression profile and identification of RhoGDI2 as a biomarker in imatinib-resistant K562 cells

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Objectives Chronic myeloid leukemia (CML) is an aggressive malignancy originating from hematopoietic stem cells. Imatinib (IM), the first-generation tyrosine kinase inhibitor, has greatly improved theliving quality of CML patients. However, owing to the recurrence and treatment failure coming from tyrosine kinase inhibitor (TKIs) resistance, some CML patients still bear poor prognosis. Therefore, we aimed to seek potential signaling pathways and specific biomarkers for imatinib resistance.Methods We performed mRNA and miRNA expression profiling in imatinib-sensitive K562 cells (IS-K562) and imatinib-resistant K562 cells (IR-K562). Differentially expressed genes (DEGs) were identified and pathway enrichment analyses were performed to explore the potential mechanism. The protein–protein interaction (PPI) network and miRNA-mRNA regulatory network were constructed to explore potential relationships among these genes. RT-qPCR, western blot and CCK8 were used for further experiments.Results A total of 623 DEGs and 61 differentially expressed miRNAs were identified. GO revealed that DEGs were mainly involved in cell adhesion, cell migration, differentiation, and inflammatory response. KEGG revealed that DEGs were typically enriched in the Rap1 signaling pathway, focal adhesion, proteoglycans and transcriptional misregulation in cancer, signaling pathways regulating pluripotency of stem cells and some immune-related pathways. The protein–protein interaction (PPI) network and miRNA-mRNA regulatory network revealed a web of diverse connections among genes. Finally, we proved that RHoGDI2 played a critical role in imatinib resistance.Conclusion The dynamic interplay between genes and signaling pathways is associated with TKIs resistance and RHoGDI2 is identified as a biomarker in IR-K562.

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