组蛋白去乙酰化酶抑制剂LBH589抑制基底样乳腺癌生长和转移

Histone deacetylase inhibitor LBH589 inhibits the growth and metastasis of basal-like breast cancer

目的:探究组蛋白去乙酰化酶抑制剂LBH589对基底样乳腺癌(BLBC)生长和转移的抑制作用。方法:通过MTT法和平板克隆实验检测LBH589对人乳腺癌细胞系MDA-MB-231和小鼠乳腺癌细胞系4T1增殖能力的影响;Transwell实验检测LBH589对细胞迁移和侵袭能力的影响;实时荧光定量PCR和免疫印迹实验检测LBH589对细胞上皮-间质转化的作用;构建4T1乳腺癌细胞Balb/c小鼠脂肪垫成瘤模型,腹腔注射LBH589,观察4T1细胞成瘤和转移能力。结果:体外实验结果显示,与对照组相比,LBH589显著抑制MDA-MB-231和4T1细胞的增殖能力(t=11.37,P<0.05;t=18.18,P<0.05)、克隆形成能力(t=7.76,P<0.05;t=15.22,P<0.05)、迁移(t=8.8,P<0.05;t=18.0,P<0.05)和侵袭能力(t=8.24,P<0.05;t=15.99,P<0.05);与对照组相比,LBH589上调细胞的上皮标志物CDH1的mRNA(t=7.33,P<0.05)表达水平,抑制细胞的间充质标志物VIM和FN1的mRNA(t=5.57,P<0.05;t=6.3,P<0.05)和蛋白(t=8.37,P<0.05;t=11.3,P<0.05)表达水平;体内实验结果表明,给予LBH589治疗显著抑制肿瘤的生长(t=6.3,P<0.05),并抑制其肺转移(P<0.05)。结论:LBH589能够抑制BLBC细胞增殖和转移,具有潜在的临床应用价值。

Objective:To investigate the inhibitory effect of histone deacetylase inhibitors LBH589 on the growth and metastasis of basal-like breast cancer.Methods:The effects of LBH589 on the proliferation,migration and invasion of human breast cancer cell line MDA-MB-231 and mouse breast cancer cell line 4T1 were determined by MTT assay,colony formation assay and Transwell assay.The effect of LBH589 on epithelial-mesenchymal transformation was detected by RT-qPCR and Western blotting.The abdominal mammary fat pads tumor-forming model of 4T1 breast cancer cells was established in Balb/c mice,and LBH589 was intraperitoneally injected to observe the effect on the tumor-forming ability of 4T1 cells and visceral metastasis.Results:Compared with control group,in vitro results showed that LBH589 significantly inhibited the proliferation(t=11.37,P<0.05;t=18.18,P<0.05),colony formation ability(t=7.76,P<0.05;t=15.22,P<0.05),migration(t=8.8,P<0.05;t=18.0,P<0.05),and invasive ability(t=8.24,P<0.05;t=15.99,P<0.05).Compared with control group,LBH589 upregulated the expression level of epithelial marker CDH1 mRNA(t=7.33,P<0.05),and inhibited mesenchymal marker VIM,FN1 mRNA(t=5.57,P<0.05;t=6.3,P<0.05)and protein(t=8.37,P<0.05;t=11.3,P<0.05).In vivo results showed that treatment with LBH589 significantly inhibited tumor growth and lung metastasis.Conclusion:LBH589 can inhibit the proliferation and metastasis of basal-like breast cancer,which has potential clinical application value.