CHD1L靶向MDM2/BMPR2在乳腺癌发生发展中的机制研究

Although CHD1L is an important oncogene in carcinogenesis, its role in breast cancer progression is elusive. Our previous study showed that CHD1L was overexpressed in breast cancer cells, but not in normal breast epithelial cells. CHD1L also promoted proliferation, migration, invasion and inhibited apoptosis in breast cancer cells. Furthermore, overexpression of CHD1L protein predicted worse disease-free survival (DFS) in breast cancer patients. All evidence above indicates that CHD1L may play important roles in breast cancer progression. We knew that CHD1L is a transcriptional factor, and we found that MDM2 and BMPR2 genes were downregulated after knocking down CHD1L expression. Interestingly, there were respectively two binding domains of CHD1L in the promoter of MDM2 and BMPR2, and these two genes also indicated poor prognosis of breast cancer patients. We hypothesize that CHD1L may affect the transcription of MDM2 and BMPR2, and finally promote breast cancer progression.Thus we will verify the role of CHD1L in the progression of breast cancer, looking for the binding domain of MDM2 and BMPR2 in order to figure out the mechanisms of CHD1L targeting MDM2 and BMPR2, then activating MDM2-p53 and BMPR2-smad1/5/8 pathways which finally promoting breast cancer progression. This study will make deep understanding about the mechanisms of breast cancer proliferation and invasion.

CHD1L是重要的癌基因，但其在乳腺癌发生发展中的作用及其机制目前尚不清楚。我们前期研究发现CHD1L在乳腺癌细胞中高表达，与增殖、凋亡、迁移、侵袭等密切相关，并可独立预测乳腺癌患者的无病生存，推测CHD1L作为一个癌基因，可能在乳腺癌的发生发展中发挥重要作用。已知，CHD1L具有转录因子功能，我们的前期研究显示， MDM2和BMPR2基因的表达与CHD1L表达一致，且其启动子区域存在与CHD1L结合的核心序列，并能预测乳腺癌患者的预后。我们推测CHD1L可能通过调控MDM2和BMPR2的转录，最终影响乳腺癌的进展。因此，我们拟在本课题中明确CHD1L与乳腺癌生物学功能的关系，并从基因水平，深入探索CHD1L靶向MDM2和BMPR2启动子的功能区域，进而激活MDM2-p53及BMPR2-smad1/5/8信号通路，促进乳腺癌增殖、侵袭的具体作用机制，为乳腺癌的发病机制提供新的理论依据。

CHD1L是重要的癌基因，但其在乳腺癌发生发展中的作用及其机制目前尚不清楚。本研究的结果表明CHD1L在近半数乳腺癌患者中高表达，其过表达与年轻、肿瘤分化差、增殖高及预后不良相关。CHD1L的过表达可促进肿瘤发生、转移、侵袭和细胞周期进程。shRNA介导的CHD1L敲减可消除CHD1L在体内外的促肿瘤作用。进一步的cDNA微阵列分析确定MDM2为CHD1L的重要下游靶标，且MDM2 / p53-EMT信号转导通路与CHD1L显著相关。为了探究CHD1L发挥功能的机制，我们通过对CHD1L过表达的人乳腺癌细胞系进行染色质免疫共沉淀-测序（ChIP）来鉴定CHD1L调控的基因。CHD1L高度结合启动子序列。对CHD1L靶向基因的细胞功能和信号通路分析表明，CHDIL与转录调控、DNA模板转录，DNA结合，蛋白质结合、内吞作用和苯丙氨酸代谢等过程相关。因此，CHD1L可通过调控下游基因的转录发挥功能。CHD1L可通过MDM2 / p53-EMT信号通路促进乳腺癌细胞的进程，MDM2可能被用作CHD1L过表达乳腺癌的治疗干预的潜在靶标。