JNK2信号通路调节肿瘤相关成纤维细胞衰老促进肿瘤转移机制研究

转移是恶性肿瘤的重要生物学特征之一，肿瘤血管新生是肿瘤生长、转移的基础。近来发现肿瘤微环境肿瘤相关成纤维细胞（TAF)对肿瘤转移具有重要调节作用，但其具体机制尚不清楚。JNK是MAPK信号通路重要组成成分，对炎性微环境中细胞衰老具有重要调节作用。本课题前期研究发现，敲除JNK2基因，可抑制肿瘤的转移、减少TAF的衰老，进而抑制肿瘤血管新生；此过程受p53调控，敲除p53基因也可抑制肿瘤转移，TAF恢复p53表达可使肿瘤转移增多。由此假设，肿瘤微环境中JNK信号通路通过影响TAF的p53依赖性衰老，进而影响肿瘤血管新生。本研究将以JNK1、JNK2、p53基因敲除鼠和临床肿瘤标本为基础，采用小鼠结肠癌肝、肺转移模型，结合体外3-D细胞共培养，利用病理分析、流式细胞分析、分子生物学方法等技术，探讨JNK信号通路在肿瘤微环境中如何抑制肿瘤血管新生的机制。这将为肿瘤的治疗提供新的理论依据。

Tumor angiogenesis is the basis of tumor growth and metastasis. Recently, Tumor associated fibroblasts (TAF) in tumor microenvironment, play an important role in tumor angiogenesis. However, the mechanisms of tumor angiogenesis is not clear. C-Jun N-terminal kinase JNK is an important component of inflammatory stress related signaling pathways, which plays an important role in cellular senescence in inflammatory microenvironment in some diseases. In previous studies, JNK2 knockout inhibited tumor metastasis, reduced TAF senescence, and inhibited tumor angiogenesis. At the cellular level, its process was regulated by p53. Therefore, we hypothesize that the JNK signal pathway in the tumor microenvironment affects tumor angiogenesis through the regulation of TAF senescence through p53. In the present study, We will test our hypothesis in JNK1 and JNK2 deficiciency mice, with transpelnic injection of SL4 colon cancer liver metastasis model, 3-D cell culture system, histologic analysis, flow cytometric analysis, molecular biology technology, and study function of JNK signal pathway in the tumor microenvironment, explore the mechanism of JNK signaling pathway on tumor angiogenesis, which may provide a new theoretical basis for tumor therapy.