pRB对DNA复制与组蛋白合成间匹配关系的调节在癌症发生中的重要作用

Evidence from epidemiological studies indicates that high-risk humanpapillomaviruses (HPVs) is the etiological agents of cervical cancer. Genomic instability is an early step and crucial event during carcinogenic progression and has been reported already in HPV-associated carcinogenesis. However, the mechanism of high-risk HPV related genomic instability has not yet been well defined in molecular detail. In our previous investigation, we generated HPV E7 expressing cell lines, then, inoculated the cells into nude mice, finally generated a tumor model. To monitor the changes of gene expression profiling during the HPV E7 associated tumorgenic progression, we completed cDNA array assay of parent cells, HPV E7 expressing cells and the tumor cells, and found that high-risk HPV E7 oncoprotein down-regulated histone expression and the loss of pRB mediated by HPV E7 might be related to the down-regulation of histone expression. Histone synthesis is strictly controlled by cell cycle and tightly coordinated with DNA synthesis because histone synthesis is essential for packaging newly replicated DNA into chromatin. In this study, we will further confirm the down-regulation of histone expression mediated by the loss of pRB and investigate the molecular mechanism and signaling pathway. We will also investigate if HPV E7 interferes the couple between histone synthesis and DNA replication through , which may be one of important causative factors of genomic instability and carcinogenesis. This studywill provides insight into the molecular mechanisms associated with pRB mediated coordination between histone synthesis and DNA replication during S phase, and the mechanism about high-risk HPV E7 induced genomic instability and tumorgenesis.

高危人类乳头瘤病毒（HPV）是宫颈癌的致癌因子，其致癌机理复杂，涉及诸 多因素，其中高危HPV 引起的基因组的不稳定是宫颈癌发生过程中的早期步骤和关键事件。 本课题以高危HPV E7 诱导的肿瘤作为病理模型，研究高危HPV 致癌过程中细胞基因组的动 态变化，发现E7 在促进DNA 复制的同时，影响组蛋白的合成，这与E7 介导的pRB 的下调有关。组蛋白的合成受细胞周期的调控，并与DNA 复制严格匹配来防止DNA 的损伤,保持细胞基因组的稳定性。我们的前期结果提示pRB 可能是细胞在S 期调节和维持DNA 复制与组蛋白合成之间的匹配关系的关键分子。本课题将进一步确认pRB 在调控DNA 复制与组蛋白合成的匹配中所起的作用，以及HPV E7 下调pRB 表达与基因组不稳定的关系,并研究上述现象的分子机理和信号通路。这将加深对细胞周期调控机制和宫颈癌发病机理的理解，有重要的学术意义。

高危人类乳头瘤病毒(HPV)是宫颈癌的致癌因子，其致癌机理复杂，涉及诸 多因素，其 中高危HPV 引起的基因组的不稳定是宫颈癌发生过程中的早期步骤和关键事件。 本课题 以高危HPV E7 诱导的肿瘤作为病理模型，研究高危HPV 致癌过程中细胞基因组的动 态变 化，发现E7 在促进DNA 复制的同时，影响组蛋白的合成，这与E7 介导的pRB 的下调有关 。组蛋白的合成受细胞周期的调控，并与DNA 复制严格匹配来防止DNA 的损伤,保持细胞 基因组的稳定性。我们的前期结果提示pRB 可能是细胞在S 期调节和维持DNA 复制与组蛋 白合成之间的匹配关系的关键分子。本课题将进一步确认pRB 在调控DNA 复制与组蛋白合 成的匹配中所起的作用，以及HPV E7 下调pRB 表达与基因组不稳定的关系,并研究上述现 象的分子机理和信号通路。这将加深对细胞周期调控机制和宫颈癌发病机理的理解，有重 要的学术意义。