摘要
目的观察组蛋白去乙酰化酶(HDAC6)在非小细胞肺癌(NSCLC)中表达的临床意义及其靶向HDAC6信号对A549细胞发生上皮间质转化(EMT)的作用机制。方法采用免疫组织化学染色法检测HDAC6和E-钙粘蛋白(E-ca)在NSCLC中的表达并分析其临床病理意义;采用转化生长因子(TGF)-β1诱导A549细胞,并予以HDAC6、Rho相关卷曲螺旋激酶(ROCK)和细胞外信号调节激酶(ERK)信号抑制剂预处理。CCK-8法检测细胞增殖,划痕实验检测细胞迁移能力,transwell实验检测细胞侵袭能力,免疫印迹法检测E-cadherin、波形蛋白(vimentin)、α-平滑肌肌动蛋白(SMA)和HDAC6的表达。结果HDAC6在NSCLC组织中高表达,与分化程度和淋巴结转移关系密切,且与E-ca表达呈负相关。TGF-β1能够诱导A549细胞发生EMT,即vimentin、α-SMA表达上调,而E-ca表达下调;予以HDAC6、ROCK和ERK信号抑制剂能够显著抑制该变化。结论HDAC6在NSCLC发生、发展中可能起到重要的调控作用,与肿瘤的EMT关系密切,其作用与ROCK和ERK信号的调控有关。
Objective To assess the clinical significance of histone deacetylase 6(HDAC6)expression in non-small cell lung cancer(NSCLC)and determine the relationship between HDAC6 and the epithelial-mesenchymal transition(EMT).Methods Tumor and noncancerous peritumoral lung tissues(controls)were collected from 52 patients with NSCLC and analyzed for HDAC6 and E-cadherin expression using immunohistochemistry.Correlation analyses between HDAC6,E-cadherin and clinicopathological parameters were performed usingχ^2 tests.In vitro studies were conducted in transforming growth factor(TGF)-β1-induced A549 cells to determine the effect of HDAC6 overexpression on molecular markers of EMT.Results Immunohistochemical analysis revealed significantly elevated HDAC6 expression in NSCLC tissues,which correlated with the differentiation stage and lymph node metastasis.Moreover,HDAC6 expression was inversely correlated with that of E-cadherin,an EMT marker.Treatment with an HDAC6 inhibitor and signaling inhibitors of Rho-associated protein kinase(ROCK)or extracellular signal-regulated kinases(ERK)significantly reduced the proliferation,migration and invasion of TGF-β1-induced A549 cells.Furthermore,western blot analysis indicated that TGF-β1 induced EMT in A549 cells,which was manifested by upregulated E-cadherin and vimentin and downregulatedα-smooth muscle actin(α-SMA).Signaling inhibitors against HDAC6,ROCK and ERK reversed the effects of TGF-β1 treatment.Conclusions Our data suggest that HDAC6 plays an important regulatory role in NSCLC tumorigenesis and progression and is closely related to tumor EMT and regulation of ROCK and ERK signaling.Targeting HDAC6 activity using HDAC6,ERK1/2 or ROCK inhibitors may be a potential therapeutic option for NSCLC.
作者
华海侠
刘瑞吉
于晓麟
赵敏
HUA Haixia;LIU Ruiji;YU Xiaolin;ZHAO Min(Department of Oncology,The First Hospital of Qinhuangdao,Qinhuangdao 063000,China;Department of Endocrinology,The First Hospital of Qinhuangdao,Qinhuangdao 063000,China;Department of Pathology,The First Hospital of Qinhuangdao,Qinhuangdao 063000,China)
出处
《中国比较医学杂志》
CAS
北大核心
2019年第8期61-67,共7页
Chinese Journal of Comparative Medicine
基金
河北省卫计委2018年度医学科学研究重点课题计划(20181185)
关键词
非小细胞肺癌
上皮间质转化
组蛋白去乙酰化酶
Rho相关卷曲螺旋激酶
细胞外信号调节激酶
non-small cell lung cancer(NSCLC)
epithelial-mesenchymal transition(EMT)
histone deacetylase 6(HDAC6)
rho-associated protein kinase(ROCK)
extracellular signal-regulated kinases(ERK)
