鼻咽癌中TRIM29的表观遗传调控及其在肿瘤发生中的作用和机制

Epigenetic alterations marked by DNA methylation are known to be frequent events during the development of nasopharyngeal carcinoma (NPC). Further, changes in methylation patterns are detectable in nasopharyngeal swabs, being of important clinical value in NPC detection and diagnosis. We found TRIM29 was hypomethylated and with high-level expression in NPC. Knockdown of TRIM29 inhibited the growth of NPC cells and induced cellular senescence. This study is aimed to clarify the hypomethylated modification of TRIM29 in NPC cells and tissues; using normal diploid fibroblasts or mouse with immune deficiency, investigate the role of TRIM29 in regulating cellular senescence and malignant transformation driven by oncogenic Ras; explore whether TRIM29 play the role in malignant transformation induced via regulating mitochondrial function, and investigate the interaction proteins of TRIM29 and the underlying mechanism; identify the correlation methylation status of TRIM29 promoter or the protein level of TRIM29 with clinical characteristics and prognosis in NPC. These data may reveal the important role of TRIM29 in NPC development, suggesting that detection of TRIM29 hypomethylation could be a promising strategy for the early detection of NPC. The data may also provide insights into the association of epigenetic modification with NPC tumorigenesis.

表观遗传学改变如DNA甲基化与鼻咽癌的发生密切相关。基因甲基化状态可在鼻咽拭子标本中被检测，因而在鼻咽癌早期诊断中具有重要的临床价值。我们的前期工作发现鼻咽癌中TRIM29基因启动子区域低甲基化修饰而表达上调，抑制TRIM29表达能显著降低鼻咽癌细胞生长能力，诱导鼻咽癌细胞衰老。本课题拟进一步明确TRIM29在鼻咽癌中的甲基化调控；在正常成纤维细胞和免疫缺陷小鼠模型中研究TRIM29是否在癌基因诱导的细胞衰老及细胞恶性转化过程中发挥作用；探讨TRIM29调控细胞衰老和细胞恶性转化是否通过影响线粒体功能，并探究其相互作用蛋白和具体分子机制；在鼻咽癌患者标本中分析TRIM29甲基化状态及蛋白表达水平与临床特征的关系。通过上述研究揭示TRIM29作为鼻咽癌发病的重要作用分子，可能成为鼻咽癌早期诊断的候选靶标，同时为表观遗传调控与鼻咽癌发生之间提供新的线索。

表观遗传学改变如DNA甲基化与鼻咽癌的发生密切相关。基因甲基化状态可被检测，因而在鼻咽癌早期诊断中具有重要的临床价值。我们的前期工作发现鼻咽癌中TRIM29基因启动子区域低甲基化修饰而表达上调，本课题进一步明确TRIM29在鼻咽癌中的甲基化调控。TRIM29能够促进表达H-RasV12的正常纤维细胞绕过OIS（Oncogene induced senescence）发生恶性转化。TRIM29蛋白表达与线粒体有共同定位，可能通过调控活性氧ROS的水平影响细胞衰老。在鼻咽癌中TRIM29表达沉默抑制细胞生长，使细胞ROS水平升高，促进细胞衰老。在鼻咽癌临床标本中TRIM29蛋白表达水平升高，且与患者临床分期密切相关。本研究项目提示TRIM29作为鼻咽癌发生的重要作用分子，可能成为鼻咽癌诊断的候选靶标。