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SCCA1 distal promoter for gene therapy of cervical intraepithelial neoplsia

SCCA1远端启动子用于宫颈上皮内瘤变的基因治疗

基本信息

批准号：
13671724
负责人：
HAMADA Katsuyuki
金额：
$ 2.62万
依托单位：
Ehime University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671724/
关键词：
squamous cell carcinoma IN cervical cancer gene therapy p53 SCCA1 promoter adenovirus SCCAI 臓器特異性転写制御扁平上皮腫瘍マーカー

项目摘要

Cervical intraepithelial neoplasia (CIN) has been increased for these 10-20 years especially in the young ages with 15-30 years, although advanced cervical cancer has been decreased for these 10-20 years. It has been strongly suggested that cervical cancer is developed by the infection of human papillomaivurs (HPV) and is infected in 90% of patients with HPV. CIN is treated by photodynamic therapy (PDT), laser treatment, cornization, but these treatment still nave some problems concerning treatment effect and steriligy. Therefore, a new method should be established for the treatment of CIN in young ages to be needed for sterility. SCCA1 gene was originally cloned from cervical cancer tissue and was expressed in cervical cancer tissue and normal squamous tissue in the cervix. In this study, we cloned and sequenced SCCA1 promoter, and characterized the promoter activity of SCCA1 promoter. To use for the determination of tissue specific promoter activity, we established cell lines of mild dysplasia, moderate dysplasia, severe dyplasia, and CIS. The proximal promoter of 500-bp upstream SCCA1 transcriptional start site was activated in invasive cervical cancer, and the distal promoter of 3.7-kb upstream SCCA1 transcriptional start site was activated in CIN cell lines. This distal promoter was introduced into adenoviru to express p53 to develop Adenovirus-SCCA1-3.7-p53 in order to determine growth inhibitory effect of this vector in invasive cervical cancer and CIN cell lines. Adenovirus-SCCA1-3.7-p53 induced strong apoptic changes especially in CIN but not in invasive cervical cancer, furthermore, showed strong growth inhibitory effect especially in CIN but not in invasive cervical cancer. From these results, it is suggested that distal promoter indroduced adenovirus vector (Adenovirus-SCCA1-3.7-p53) has the potential to treat CIN.

尽管晚期宫颈癌在这10-20年间有所减少，但宫颈上皮内瘤变(CIN)在这10-20年间有所增加，尤其是在15-30岁的年轻人群中。强烈认为宫颈癌是由人乳头瘤病毒（HPV）感染引起的，90%的患者都感染了HPV。 CIN的治疗方法有光动力疗法(PDT)、激光治疗、角化术等，但这些治疗方法仍存在一些治疗效果和无菌性问题。因此，应建立一种治疗年轻不育患者CIN的新方法。 SCCA1基因最初是从宫颈癌组织中克隆出来的，在宫颈癌组织和宫颈正常鳞状组织中表达。在本研究中，我们克隆并测序了SCCA1启动子，并表征了SCCA1启动子的启动子活性。为了用于测定组织特异性启动子活性，我们建立了轻度不典型增生、中度不典型增生、重度不典型增生和CIS细胞系。 500 bp上游SCCA1转录起始位点的近端启动子在浸润性宫颈癌中被激活，而3.7 kb上游SCCA1转录起始位点的远端启动子在CIN细胞系中被激活。将此远端启动子引入腺病毒中表达p53，开发腺病毒-SCCA1-3.7-p53，以确定该载体在浸润性宫颈癌和CIN细胞系中的生长抑制作用。腺病毒-SCCA1-3.7-p53诱导强烈的细胞凋亡变化，特别是在CIN中，但在浸润性宫颈癌中则不然，此外，显示出强烈的生长抑制作用，特别是在CIN中，但在浸润性宫颈癌中则不然。从这些结果表明，远端启动子引入的腺病毒载体（腺病毒-SCCA1-3.7-p53）具有治疗CIN的潜力。