| Objective : Diffused large B-cell lymphoma(DLBCL)is the most common pathological type of non-hodgkin lymphoma(NHL)and accounts for about one-third of adult NHL.DLBCL has significant heterogeneity.Although Rituximab has improved the long-term survival of patients,about 1/3 of patients are still suffering from refractory or eventually relapsing diseases.Once the disease relapses,patients are more insensitive to second-and third-line chemotherapy regimens.Many studies have shown that there is an interaction between lymphoma cells and tumor microenvironment(mainly composed of stromal cells),which has a profound influence on the biological behavior of lymphoma cells.Studies in the last two decades have shown that mi RNAs are differentially expressed in a variety of solid tumors and hematologic system tumors,suggesting that mi RNAs may affect tumor progression.Moreover,studies suggest that mi RNAs may also serve as new molecular targets for tumor treatment.Histone deacetylases(HDACs)are a family of key enzymes that affect tumor epigenetic changes.However,extensive,non-selective inhibition of HDACs has led to a variety of toxic and side effects,limiting its clinical application.Therefore,it is urgent to select HDAC and specific inhibitors that are significantly related to tumor.However,whether micro RNA and HDAC3 play a role in promoting DLBCL cell growth and mediating drug resistance in tumor microenvironment,and whether HDAC3 inhibitors can promote DLBCL cell growth and overcome drug resistance is still unclear.Therefore,this study further explored the role and detailed mechanism of micro RNA and HDAC3 in promoting DLBCL cell growth and mediating drug resistance in tumor microenvironment.Methods:In this study,the role and mechanism of mi RNA-26a/HDAC3 in promoting DLBCL cell growth and mediating drug resistance in stromal cells were investigated by mi RNA microarray analysis,R-T PCR,western blot and NOD/SCID animal model in vivo on the basis of co-culture of DLBCL cells with MSC.Results:1.mi RNA-26 a plays a key role in stromal cells promoting the growth of DLBCL cells1)mi RNA microarray analysis showed that after co-culture with stromal cells,the expressions of mi RNA-15,mi RNA-16,mi RNA-26 a in DLBCL cells were decreased,and the fold changes≥2;2)RT-PCR verificated that after co-culture with stromal cells,mi RNA-26 in DLBCL cells was significantly down-regulated;3)High expression of mi RNA-26 a overcomes stromal cell-mediated drug resistance.2.HDAC3 plays a key role in stromal cells promoting the growth of DLBCL cells1)After co-culture with stromal cells,the HDAC3 protein expression level is increased in DLBCL cells;2)HDAC3 inhibitor RGFP966 inhibits the proliferation of DLBCL cells;3)HDAC3 inhibitor RGFP966 inhibits the activation of AKT and STAT3 signaling pathways.3.The regulatory role of mi RNA-26 a /HDAC3 in stromal cell-mediated DLBCL cell drug resistance1)mi RNA-26 a inhibits the expression level of HDAC3 protein in DLBCL cells2)The high expression of mi RNA-26 a and the HDAC3 inhibitor RGFP966 synergistically inhibited the proliferation and promoted apoptosis of DLBCL cells.4.The vitro and vivo experiments showed that HDAC3 inhibitor RGFP966 overcomes stromal cell-mediated DLBCL cells drug resistance.5.Synergistic effect of HDAC3 inhibitor RGFP966 and EZH2 inhibitor DZNep/ BTK inhibitor Ibrutinib other targeted drugs in the treatment of DLBCL.Conclusion:In the DLBCL tumor microenvironment,tumor stromal cells negatively regulate the high expression of HDAC3 by down-regulating mi RNA-26 a in DLBCL cells,activate its downstream AKT and STAT3 signaling pathways,promote the growth of DLBCL cells and mediate drug resistance. |
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