X型胶原蛋白α1通过DDR2/pERK/pSnail1途径促进结直肠癌肝转移的作用及机制

Colorectal cancer liver metastasis(CRCLM), the most common metastatic form of colorectal cancer(CRC) , is the main cause of CRC patients death . Nowadays the pathogenesis of CRCLM is unclear, thus there is no specific targeted diagnosis and treatment program. Our previous study found that high expression level of Collagen Type X alpha 1 Chain （COL10A1） was closely related to the poor prognosis of CRC patients. The high expression level of COL10A1 promoted Epithelial Mesenchymal Transition（EMT） in CRC cells and enhanced the invasion and migration abilities of CRC cells in vitro. The preliminary results suggested that the high expression level of COL10A1 was also associated with the poor prognosis of CRCLM patients and promoted CRCLM progression in the spleen injection liver metastasis model in vivo. Moreover, high expression of COL10A1 may interact with DDR2 receptor, up-regulate pERK levels, then up-regulate pSnail1 protein level and promote its nuclear translocation, COL10A1 can also protect pSnail1 from ubiquitination, as well known，pSnail is a key molecule that mediates EMT. This project intends to clarify the exact role of COL10A1 in CRCLM progression through DDR2/pERK/pSnail1 pathway, and explore the molecular mechanism of the COL10A1 regulating the CRCLM progression through the DDR2/pERK/pSnail1 pathway. The project will complement the molecular mechanism of CRCLM progression, and hope to provide new and effective diagnosis and treatment targets for CRCLM patients.

结直肠癌肝转移（CRCLM）是结直肠癌（CRC）最常见转移方式，也是CRC患者死亡的最主要原因，其发生机制不明晰，因而缺乏针对性治疗。前期研究发现X型胶原蛋白α1(COL10A1)高表达CRC患者生存预后更差，其高表达促进CRC细胞发生上皮间质化（EMT），提高CRC细胞侵袭转移能力。预实验结果提示COL10A1高表达促进CRC细胞动物体内发生肝转移，并与CRCLM患者不良预后相关。COL10A1可能与DDR2受体相互作用，上调pERK水平，进而上调pSnail1蛋白水平并促进其核转位，并减缓pSnail1泛素化进程，而pSnail是介导EMT的关键分子。因此本项目拟明确COL10A1促进CRCLM的生物学作用，并进一步探索COL10A1通过DDR2/pERK/pSnail1途径介导EMT促进CRCLM的分子机制，完善CRCLM分子调控网络，期望为CRCLM的精准治疗提供新的靶点。

结直肠癌肝转移（CRCLM）是结直肠癌（CRC）常见转移方式，也是CRC患者死亡的最主要原因，其发生机制不明晰，因而缺乏针对性治疗。前期研究发现X型胶原蛋白α1（COL10A1）高表达CRC患者生存预后更差，其高表达促进CRC细胞发生上皮间质化（EMT），提高CRC细胞侵袭转移能力。本项目研究提示COL10A1高表达促进CRC细胞动物体内发生肝转移, 并与CRCLM患者不良预后相关。具体SOX9可能调控COL10A1表达，COL10A1与DDR2受体相互作用后促进肿瘤细胞发生EMT，进而促进CRCLM。本项目初步阐明了COL10A1促进CRCLM的生物学作用，并进一步探索了COL10A1受SOX9调控介导EMT促进CRCLM的分子机制，进一步完善了CRCLM分子调控网络，有可能为CRCLM的精准治疗提供新的靶点。

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