MORC2 对C/EBPα 转录活性的调控以及对肿瘤发生的影响机制研究

Disruption of normal differentiation and proliferation is a critical component of tumorigenesis, especially in breast cancer, but the mechanisms of this process remain elusive. C/EBPα is a critical tissue-specific transcription factor that controls both of this process and proliferation arrest, thereby play a pivotal role in the determination of cellular fate. In addition, recent studies suggest that cancer stem cells (CSCs) have important roles in tumor formation. .During our previous study, GST pull-down assay results indicated that Microrchidia (MORC) family CW-type zinc-finger 2 (MORC2) could interact with TE-Ⅲ domain of C/EBPα, which overlaps with the SUMO-1 conjugation lysine residue 161 site. Western blot results indicated that overexpression of C/EBPα promoted the sumoylation of C/EBPα, which might affect its transactivation. MORC2 might inhibit C/EBPα-mediated differentiation by inducing C2C12 cell differentiaton and colony formation assays using the stable expressing MORC2 breast cancer cell lines, suggesting that MORC2 as an important negative regulator of C/EBPα expression causes the switch from a cellular differentiation to a cellular proliferation program to induce tumorigenesis. Meanwhile, the correlation between MORC2 and CSCs will be studied. Taken together, this study will provide a novel target for the brest cancer diagnosis and treatment by nude mouse model assay and clinical case statistics.

C/EBPα具有组织特异性且能决定细胞命运的关键转录因子，在维持细胞分化与增殖中起重要作用。它的表达与乳腺等肿瘤有关，但发生机制还很不清楚。调节C/EBPα转录活性及肿瘤干细胞等机制都可能引起肿瘤发生。GST pull-down显示MORC2能与C/EBPα的含有161赖氨酸SUMO位点的TE-Ⅲ转录激活域结合。Western Blot显示过表达的MORC2促进了C/EBPα的Sumoylation 水平，这可能影响了其转录活性和细胞分化能力，也提示可能参与肿瘤干细胞的调节有关。本项目将以马血清C2C12细胞分化模型和稳定表达MORC2的乳腺癌细胞系等一些分子细胞生物学手段来阐明二者关系对细胞分化和增殖的影响，利用动物实验和临床乳腺癌组织样本验证MORC2和C/EBPα与乳腺癌发生及预后的关系，弄清二者关系在肿瘤发生中的作用及其机制，为乳腺癌的诊断和治疗提供新的理论依据

C/EBPα具有组织特异性且能决定细胞命运的关键转录因子，在维持细胞分化与增殖中起重要作用。它的表达与胃癌等肿瘤有关，但发生机制还很不清楚。调节C/EBPα转录活性及肿瘤干细胞等机制都可能引起肿瘤发生。我们实验结果显示MORC2能与C/EBPα的含有161赖氨酸SUMO位点的TE-Ⅲ转录激活域结合，过表达的MORC2促进了C/EBPα的Sumoylation 水平，这抑制其转录活性并促进了其细胞分化能力。本项目以马血清C2C12细胞分化模型和稳定表达MORC2的胃癌细胞系等一些分子细胞生物学手段来阐明二者关系对细胞分化和增殖的影响，利用动物实验和临床胃癌组织样本验证MORC2和C/EBPα与胃癌发生及预后的关系，弄清二者关系在肿瘤发生中的作用及其机制，为胃癌的诊断和治疗提供新的理论依据。