基于染色质结构分析的食管癌放疗增敏新机制研究

Esophageal cancer, including esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma, is one of the leading causes of cancer-related death, and its incidence was increasing year by year in the world. Radiotherapy is one of the main methods of esophageal carcinoma. However, the sensitivity to radiation is quite different, which to some extent limited the clinical application of radiotherapy. How to enhance the radiosensitivity of esophageal cancer is still an unresolved problem. As a noval kind of antitumor drug for chemotherapy, TSA is a classic inhibitor of histone deacetylases (HDAC) with potential perspective in clinical application. In our previous work, we found that TSA treatment altered the acetylation stutas of core histone at a very low concentration. Analysis of its biologic effect on viability in EC109 cells showed TSA increased the death rate via cell apoptosis and decreased the clonogenic survival after radiation. These results indicated TSA treatment enhanced the radiosensitivity of EC109 cells. As is known, TSA is an inhibitor of HDAC, which can alter the higher structure of chromatin via modification of histone acetylation. So, we speculated that the enhanced radiosensitivity of EC109 cells was related to the altered chromatin structure. Based on our previous data, in current project we will further investigate the alteration of chromatin structure induced by TSA, and explore its effects on cell radiosensitivity. We are also interested in the signal pathway of MAPK to find out its molecular mechanism. This project helps to discover the new molecular mechanism of TSA and deeply understand the relationship between chromatin structure and radiation, which will benefit the clinical application of radiotherapy.

食管癌为我国常见上消化道肿瘤，严重危害人类健康。放疗是食管癌治疗的主要方法之一，由于部分患者对射线敏感性差而限制了其应用。近年来，组蛋白去乙酰化酶抑制剂在肿瘤治疗中显示出良好的应用前景，代表之一就是TSA。我们的前期研究发现，低浓度TSA即可引起食管癌细胞组蛋白乙酰化水平明显改变。生物学效应分析显示该药可以增强食管癌细胞在放射后的急性死亡、降低克隆形成能力。这些结果提示：TSA可以增加食管癌细胞放射敏感性。由于它可以引起组蛋白乙酰化水平改变，与染色质结构密切关联。因此，我们推测该药增强细胞辐射敏感性与染色质高级结构改变密切相关。本项目拟以食管癌细胞为对象进一步探讨TSA所引起的染色质结构改变与其生物学效应的关系，阐明其增强食管癌细胞放射敏感性的有效性及机制；然后检测与之相关的MAPK信号分子，分析其信号传递途径。本研究可揭示电离辐射致肿瘤细胞损伤的新机制，对临床肿瘤放疗具有重要指导意义。

食管癌为我国常见上消化道肿瘤，严重危害人类健康。放疗是食管癌治疗的主要方法之一，由于部分患者对射线敏感性差而限制了其应用。近年来，组蛋白去乙酰化酶抑制剂在肿瘤治疗中显示出良好的应用前景，代表之一就是TSA。我们的前期研究发现，低浓度TSA 即可引起食管癌细胞组蛋白乙酰化水平明显改变。生物学效应分析显示该药可以增强食管癌细胞在放射后的急性死亡、降低克隆形成能力。这些结果提示：TSA 可以增加食管癌细胞放射敏感性。由于它可以引起组蛋白乙酰化水平改变，与染色质结构密切关联。故在本项目中，我们以食管癌细胞为对象明确了TSA 所引起辐射增敏效应，且在其它类型的肿瘤细胞中也有相同的作用。我们进一步检测显示TSA可以引起食管癌细胞染色质结构改变，这与其生物学效应密切相关。这从机制上阐明TSA增强食管癌细胞放射敏感性的分子机制。在本项目中，我们选择了其靶点之一的Rad9A分子，分析了其在辐射中的生物学功能。之后，我们还检测与之相关的MAPK 信号分子，分析其信号传递途径。最后，我们还对染色质结构调节分子HDAC1的功能进行了分析，初步探索了其相互作用的蛋白。本项目研究历时四年，已经发表SCI论文四篇，申请并获得授权专利一项。本研究可揭示电离辐射致肿瘤细胞损伤的新机制，对临床肿瘤放疗具有重要指导意义。