Study Of Histone Deacetylase On The Target Therapy Of Uterine Cervical Cancers

Objectives:To investigate the significance of clinical pathology of Histone Deacetylase(HDACs) expression in uterine cervical lesions,and to evaluate the killing effect of HDACs inhibitor,trichostatin A(TSA),for the molecular target therapy of uterine cervical cancers.Materials and Methods:Total 225 cases of paraffin embedded cervical lesion blocks,including 8 cases of normal cervical epithelium,52 cases of cervical intraepithelial neoplasia(CIN),141 cases of squamous cell carcinomas(SCC),and 24 cases of adenocarcinomas were selected from Dept.of Pathology,Yanbian University Hospital,Yanbian Women's Hospital, and Korea University Medical Center in the period of 1996-2006.The protein expression of HDAC1,2,3,5,6 were detected by immunohistochemical method, Western Blot,and immunofluorescence staining.For investigating the killing effect and mechanism of TSA on cervical cancers,short interfering RNA of HDAC6 transfection,XTT assay,and flow cytometry were used.Results:The positive rate of all HDAC1,3,5,6 protein is 0(0/8),12.5%(1/8),5%(2/8),0(0/8) in normal cervical epithelium,respectively.The positive rate of HDAC1 is 82.7%in CIN (43/50),83%in SCC(117/141),91.7%in adenocarcinomas(22/24);HDAC3 is 58.7% in CIN(27/46),62.4%in SCC(87/141),70.8%in adenocarcinomas(17/24);HDAC5 is 66%in CIN(33/50),63.14%in SCC(89/141),75%in adenocarcinomas(18/24). And all of HADC1,2,3,and HDAC5 are nuclear staining pattern.Meanwhile,HDAC6 is the cytoplasmic staining pattern,and the positive rate is 84.6%in CIN(44/52), 83.0%in SCCs(117/141),91.7%in adenocarcinomas(22/24).However,HDAC2 is negative in all of normal cervical epithelium,and the majority of CIN and cervical cancer cases showed weak positive,only a few cases are positive for HDAC2. Additionally,HeLa and CaSki cervical cancer cells are very sensitive for TSA treatment,but the primary keratinocyte is not.Also,the ratio of apoptosis and cell death were significantly higher in TSA treated HeLa cells than in control group,and the acetylated tubulin is up-regulated in TSA treated HeLa cells.Conclusions: The HDAC1,3,5,6 over expression are useful affiliated markers for the early diagnosis of uterine cervical cancer and CIN.The HDACs inhibitor,TSA,can kill the uterine cervical cancer cells effectively,the up-regulated of acetylated tubulin and apoptosis induction maybe the mechanisms of the killing effect.