Abstract
Doxorubicin resistance is a major challenge in the successful treatment of canine diffuse large B-cell lymphoma (cDLBCL). In the present study, MethylCap-seq and RNA-seq were performed to characterize the genome-wide DNA methylation and differential gene expression patterns respectively in CLBL-1 8.0, a doxorubicin-resistant cDLBCL cell line, and in CLBL-1 as control, to investigate the underlying mechanisms of doxorubicin resistance in cDLBCL. A total of 20289 hypermethylated differentially methylated regions (DMRs) were detected. Among these, 1339 hypermethylated DMRs were in promoter regions, of which 24 genes showed an inverse correlation between methylation and gene expression. These 24 genes were involved in cell migration, according to gene ontology (GO) analysis. Also, 12855 hypermethylated DMRs were in gene-body regions. Among these, 353 genes showed a positive correlation between methylation and gene expression. Functional analysis of these 353 genes highlighted that TGF-β and lysosome-mediated signal pathways are significantly associated with the drug resistance of CLBL-1. The tumorigenic role of TGF-β signaling pathway in CLBL-1 8.0 was further validated by treating the cells with a TGF-β inhibitor(s) to show the increased chemo-sensitivity and intracellular doxorubicin accumulation, as well as decreased p-glycoprotein expression. In summary, the present study performed an integrative analysis of DNA methylation and gene expression in CLBL-1 8.0 and CLBL-1. The candidate genes and pathways identified in this study hold potential promise for overcoming doxorubicin resistance in cDLBCL.
Highlights
Canine diffuse large B-cell lymphoma is one of the most frequently diagnosed malignancies in dogs
Multidrug chemotherapy that is doxorubicin-based remains the treatment of choice and extends the life span of dogs affected by Canine diffuse large B-cell lymphoma (cDLBCL); cDLBCL remains incurable, with variable survival time and high relapse rates due to drug resistance [1, 2]
TGF-β signaling was significantly increased in HCT116 human colon cancer cells treated with doxorubicin, and inhibition of TGF-β signaling markedly increased the sensitivity of HCT116 cells to doxorubicin [24], suggesting the role of elevated TGF-β signaling in resistance to doxorubicin
Summary
Canine diffuse large B-cell lymphoma (cDLBCL) is one of the most frequently diagnosed malignancies in dogs. Doxorubicin resistance in canine B cell lymphoma characteristic translocations and molecular abnormalities, as well as similar therapeutic responses to chemotherapy [1]. Multidrug chemotherapy that is doxorubicin-based remains the treatment of choice and extends the life span of dogs affected by cDLBCL; cDLBCL remains incurable, with variable survival time and high relapse rates due to drug resistance [1, 2]. Since drug resistance is the major limiting factor in the successful treatment of cDLBCL with doxorubicin-based chemotherapy, understanding the mechanisms causing drug resistance will significantly improve therapeutic strategies for fighting cDLBCL and increase the survival rates. It is critical to understand the DNA methylation profile of resistant cDLBCL to achieve a breakthrough in cancer treatment
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