低密度脂蛋白胆固醇（LDL）激活TGF-β信号通路促进结直肠癌上皮间质转化的分子机制研究

Colorectal cancer (CRC) is one of the most common malignant diseases, while epithelial mesenchymal transition (EMT) is closely associated with invasion and metastasis of cancer, and TGF-β pathway is one of the most well characterized and important signaling pathways to induce EMT. Our group demonstrated that LDL significantly enhances CRC EMT, and LDL significantly increases the expression of Smad2/3, which is one of the key molecules of TGF-β signaling pathway, and we also found that LDL enhances ROS level, and migration and stemness of CRC cells. Based on the previous study, this project aims to analyze the effect of LDL in CRC cell EMT; and to analyze the specific molecule of LDL in CRC EMT pathways by nhabiting the molecules in TGF-β signaling pathway via RNA interference, and eliminating ROS to examine the mechanism by which LDL affects the relevant molecular in EMT. This project would help to identify the function of LDL in CRC EMT and the relevant mechanism, and to provide evidence for the possibility of LDL and relevant molecules as therapeutic targets of CRC. This research has a vital scientific significance and potential clinical value.

结直肠癌是全球范围内最常见的恶性肿瘤之一，上皮间质转化（EMT）与肿瘤侵袭、转移等密切相关，其中TGF-β通路是EMT研究最深入、最重要的信号通路之一。我们前期研究发现，低密度脂蛋白胆固醇（LDL）可诱发结直肠癌细胞EMT，显著影响TGF-β通路关键分子Smad2/3表达，证实了LDL显著提高结直肠癌细胞ROS水平、增强其迁移能力和细胞干性。本课题在前期研究基础上，拟进一步研究LDL在结直肠癌EMT中的生物学效应；通过RNA干扰技术逐级敲低TGF-β信号通路下游蛋白表达，探究LDL在EMT中的作用分子；通过清除ROS，探讨LDL调控其作用分子的机制；并从结直肠癌进展的角度进一步阐明LDL及其作用分子的临床生物学意义。本课题有助于明确LDL在结直肠癌EMT中的生物学效应和作用机制，为LDL及其作用分子作为结直肠癌治疗靶点提供依据，具有重要科学意义及潜在临床应用价值。

结直肠癌（colorectal cancer, CRC）是全球范围内最常见的恶性肿瘤之一，目前认为，大肠正常粘膜-腺瘤-腺癌以及伴随的基因突变是CRC发生的经典模式；大量研究显示，高脂饮食和较高的低密度脂蛋白胆固醇（low density lipoprotein cholesterol, LDL）水平可显著促进这一过程。在动物体内实验层面，本课题组研究发现高脂饮食喂养可显著提高裸鼠体内LDL水平，增加裸鼠转移瘤水平。临床数据相关性分析表明结直肠腺瘤患者LDL水平高于对照组，且伴肝转移结直肠癌患者LDL水平显著高于无转移结直肠癌患者。进一步探究LDL在EMT中的作用发现，LDL可诱发结直肠癌细胞EMT，提高结直肠癌细胞迁移、侵袭能力,显著影响TGF-β通路关键分子Smad3表达。通过RNA干扰技术敲降Smad3，可显著逆转LDL处理导致的结直肠癌细胞迁移、侵袭能力的增强以及细胞上皮标记物E-cadherin的下调，间质标记物N-cadherin、Vimentin、slug的上调。更进一步研究发现，LDL可促进Smad3磷酸化入核发挥效应。本项目阐述了LDL在结直肠癌EMT中的生物学效应和作用机制，为LDL及其作用分子作为结直肠癌治疗靶点提供依据，具有重要科学意义及潜在临床应用价值。