p-MSK1 (Thr581)影响结直肠癌预后的机制研究

项目名称： p-MSK1 (Thr581)影响结直肠癌预后的机制研究

项目编号： No.81201545

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学1

项目作者： 傅新晖

作者单位： 中山大学

项目金额： 23万元

中文摘要： MSK1激酶是MAPK通路的下游分子，其Thr581位点经磷酸化激活后可促癌变，但其致癌机制研究甚少。我们发现，结直肠癌不良预后仅与MSK1激酶Thr581位点磷酸化水平有关，而与MSK1总蛋白表达无关，且MSK1的抑制剂H89可明显抑制HCT116肠癌细胞增殖，同时降低了p-MSK1 (Thr581)水平和转录因子AP-1转录水平，据此我们推测p-MSK1 (Thr581)水平增高后可通过上调AP-1促增殖。本研究拟1）探讨MSK1激酶活性对结直肠癌细胞增殖、迁移、侵袭和转移能力的作用；2）明确AP-1是否介导了MSK1激酶活性对结直肠癌细胞的影响；3）明确结直肠癌中p-MSK1 (Thr581)水平、AP-1组成元件（c-JUN、c-FOS）之间是否有相关性及其临床意义。本项目的完成，可明确MSK1激酶活性对结直肠癌细胞的作用及其机理，为结直肠癌的治疗提供新思路。

中文关键词： MSK1；结直肠癌；生物标记物；预后；

英文摘要： Mitogen- and stress-activated kinase 1 (MSK1) is a downstream molecule of MAPK pathway. It can be activated by phosphorylation at Thr581. p-MSK1 (Thr581) has a role in carcinogenesis. However, mechanisms about p-MSK1 (Thr581) involved in carcinogenesis are not well understood. Our previous study showed that only p-MSK1 (Thr581), not total MSK1, is a prognosis marker of colorectal cancer patients. We also found that H89, an inhibitor of MSK1, can dramatically repress the proliferation of HCT116 cells. Meanwhile, H89 treatment can decrease the expression of p-MSK1 (Thr581) and transcription levels of AP-1. Based on these results, we assume that p-MSK1 (Thr581) may affect CRC prognosis through AP-1. In the present study, we are going to explore whether p-MSK1 (Thr581) can affect CRC cells' proliferation, migration and invasion ability. To prove whether AP-1 is meditated by p-MSK1 (Thr581) in colorectal cancer is the second aspect of our study. Last, the clinical significance of AP-1 expression will be evaluated by tissue arrays. The results of this study can provide valuable information for the function of p-MSK1 (Thr581) in colorectal cancer and for the target-therapy.

英文关键词： Mitogen- and stress-activated protein kinase 1；CRC；Biomarker；Prognosis；