MDSC通过分泌CCL7激活JAK/STAT3信号轴调控结直肠癌肝转移休眠细胞活化的分子机制

肿瘤休眠是瘤细胞逃避治疗并最终导致肿瘤转移复发的重要原因，髓源性抑制细胞（MDSCs）在肿瘤转移休眠中的作用尚未见报道。前期工作中，我们成功构建了结直肠癌肝转移休眠模型，发现MDSCs可促进结直肠癌肝转移休眠细胞的增殖，结合基因芯片筛选及预实验结果，提出一个新机制：MDSCs通过分泌CCL7与结直肠癌转移休眠细胞膜上CCR2受体结合，激活JAK-STAT3信号通路，上调其靶基因c-Myc及CyclinD1等表达，从而促进结直肠癌转移休眠细胞的增殖活化。本研究拟从细胞、动物及临床标本等水平（1）明确MDSCs在结直肠癌肝转移休眠细胞增殖活化中的作用；（2）验证MDSCs通过分泌CCL7激活JAK/STAT3信号通路并上调其增殖相关靶基因；（3）检测MDSCs、CCL7分子在结直肠癌转移预测及治疗中的潜在应用。旨在揭示肿瘤转移休眠的一个新机制，为临床预测、控制肿瘤转移提供新的靶点和治疗策略。

Tumor dormancy is the main cause of avoiding treatment and eventually developing metastasis of tumor cells. Till now, the role of myeloid-derived suppressor cells (MDSCs) in tumor metastatic dormancy is unknown. In our previous study, we succesfully established the liver metastatic dormancy mice model of colorectal cancer and found that MDSCs promoted the proliferation of liver metastatic dormancy cells. Based on cDNA chip screening and a series of experiments, we put forward a novel molecular mechanism: MDSCs promotes the proliferation of liver metastatic dormancy cells by secreting CCL7, which binds with CCR2 receptor in metastatic dormancy cells, and activating JAK-STAT3 signaling pathway and subsequently up-regulated the levels of downstream targets c-Myc and CyclinD1. This study will verify the hypothesis at the levels of cell lines, animal and clinical samples. (1) To define the role of MDSCs in the activation of CRC liver metastatic dormant cells; (2) To verify that CCL7 secreted by MDSCs activates JAK/STAT3 pathway and then upregulates its downstream genes; (3) To evaluate the potential value of MDSCs, CCL7 on metastasis prediction and therapy in colorectal cancer patients. This study aims to reveal a novel mechanism of tumor metastatic dormancy and provide the novel targets and therapy strategy for predicting and controlling tumor metastasis.