HPV整合至宿主染色体4q31区段后导致宫颈癌发生发展的关键基因筛选及机制研究

Infection with high-risk human papillomavirus (HPV) is a prerequisite for the development of cervical cancer. Although this theory has been widely accepted, HPV alone is not sufficient for the progression to invasive cancer. In spite of the recent progress in molecular aspects of cervical cancer, the genetic basis of progression of HR-HPV infection to invasive cancer in the multi-step progression of cervical cancer remains poorly understood. During previous studies about integration of HPV to the host genome, we found patients with which HPV integrated into host chromosomal 4q31 region possess the specific gene expression profiling and biological characteristics. It suggested that the integration of HPV to the host chromosomal 4q31 region may be a kind of cervical cancer with specific pathogenesis and clinical features. These phenomena haven't been reported to date. In the present study, we planed to screen candidate genes by Custom Fine-Tiling Array, determine the key susceptibility gene in clinical samples, identify signaling pathways perturbed by silence or overexpression the candidate key susceptibility gene in cell and animal models and describe the pathogenesis of this special kind of cervical cancer. This project sought to investigate the key target gene after HPV integrated into host chromosomal 4q31 region and to provide supporting deta for new strategies in the treatment of cervical cancer. We hope this research will be helpful to the molecular classification of the whole cervical cancer patients through dissecting the specific penomenon of the integration of HPV to the host chromosomal 4q31 region.

高危型HPV感染是宫颈癌的主要风险因素，然而大部分感染HPV的患者并未发展为宫颈癌，其具体致癌机制目前并未阐明。在检测HPV的整合位点的工作中，申请者意外发现HPV整合于宿主4q31区段的患者具有特殊的基因表达指纹和生物学特征，这一现象目前在国内外均未见报道，强烈提示HPV整合至宿主4q31区段可能是一种具有特殊发病机理和临床特征的宫颈癌类型。因此，本项目拟筛查HPV整合在宿主染色体4q31区段后的关键靶基因，同时在较大样本、不同发病阶段宫颈病变中进一步验证靶基因表达与宫颈癌分级分期及预后的关系，并通过体外和体内实验明确靶基因在宫颈癌发生发展中的作用机理。从而达到识别病毒特殊位点整合后的关键"靶标"、为合理设计宫颈癌治疗新策略提供新的理论基础等目的，以期从HPV定点整合至宿主4q31区段这一特殊现象窥视宫颈癌整个群体的分子分型研究。

本项目通过临床样本的HPV整合测序，发现HPV整合在宿主染色体的关键靶基因之一MAPK，应用荧光原位杂交技术直观验证出MAPK与HPV16整合位点的定位关系。明确定位关系后，进一步在在大样本、不同发病阶段宫颈病变组织标本中对MAPK蛋白的表达进行了验证，确定了在宫颈癌前病变阶段，MAPK的表达与HPV16 E7的表达呈正相关，而在不同级别宫颈癌组织标本中，未发现类似趋势，提示MAPK的表达在宫颈癌前病变的进展过程中发挥了重要作用，可能作为阻断宫颈癌前病变向宫颈癌进展的一个潜在靶标。

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