Asporin通过Smad3促进结直肠癌进展及其机制研究

ASPN（Asporin）是定位于胞浆的结直肠癌潜在标记物，但其调控结直肠癌的具体机制尚未完全明确。我们发现ASPN在结直肠癌中有CNV改变与蛋白过表达现象，该蛋白高表达患者预后较差。初步功能研究发现ASPN能促进结肠癌细胞生长与运动，抑制凋亡；免疫共沉淀发现其与Smad3存在胞内相互作用。本研究拟在此基础上，探索ASPN在结直肠肿瘤发生发展不同阶段病变的效应及机制：①在更大规模样本的不同病理诊断结直肠组织中检测ASPN的CNV及蛋白表达；②在裸鼠成瘤模型，以及结直肠癌不同发展阶段组织来源的Colonoids中检测ASPN干扰对表型的影响；③明确ASPN与Smad3的相互作用及相关信号通路，探索其直接效应及下游机制；④通过挽救实验明确Smad3及下游因子在ASPN调控结直肠癌中的作用。本研究将为结直肠癌的机制研究及治疗提供新的实验依据。

ASPN (Asporin) is a potential marker of colorectal cancer located in the cytoplasm, but its regulatory effects and the related mechanisms in colorectal cancer are not clear. CNV amplification and protein overexpression of ASPN were identified in colorectal cancer. The patients with high ASPN level exhibited worse prognosis than others. Our preliminary assays suggested that ASPN promoted the growth and movement of colorectal cancer cells, and suppressed apoptosis. Further co-immunoprecipitation assays indicated its intracellular interaction with Smad3. Based on these results, we aimed to explore the effects and mechanisms of ASPN in colorectal caner of different stages: ①To detect the CNV and protein expression of ASPN in colorectal tissue with different pathological diagnosis; ②Using xenograft model and colonoids derived from different stages of colorectal cancer tissues, to detect ASPN's effects on phenotypes; ③To clarify the details of the interaction between ASPN and Smad3, and explore the direct effects and downstream mechanisms; ④Using rescue experiments to verify the role of Smad3 and downstream factors in ASPN regulated cancer progression. This study will provide new experimental evidence on the pathogenesis of colorectal cancer, and enlighten research ideas in development of novel therapeutic targets.