Zhu Xu, Sun Li, Lan Jingqin, Xu Linli, Zhang Meng, Luo Xuelai, Gong Jianping, Wang Guihua, Yuan Xianglin, Hu Junbo, Wang Jing
Cancer Research Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Oncotarget. 2016 Jun 14;7(24):36501-36509. doi: 10.18632/oncotarget.9038.
Tumor lymphangiogenesis is an important early event in tumorigenesis, one that promotes lymphatic metastasis. BRG1 (also known as SMARCA4) is a central component of the SWI/SNF chromatin-remodeling complex. In a previous work, we have reported that decreased BRG1 could promote colon cancer cell migration and invasion, and that the BRG1 expression level is negatively correlated with lymphatic metastasis. In the current study, we provide a comprehensive analysis of the role of BRG1 during lymphangiogenesis in colorectal cancer. Lymphatic vessels are more abundant in BRG1 low-expression tumors than in BRG1 high-expression tumors. We investigate the process by which BRG1 can promote VEGFC transcription and induce lymphangiogenesis in vivo and in vitro. We show that BRG1 controls lymphangiogenesis by binding to STAT3 and regulating STAT3 activation. We also prove the mechanisms through clinical samples. In summary, our demonstration of the important roles of the BRG1/STAT3/VEGFC in tumor-associated lymphangiogenesis might lead to the discovery of novel therapeutic targets in the treatment of cancers with BRG1 loss of function.
肿瘤淋巴管生成是肿瘤发生过程中的一个重要早期事件，它促进淋巴转移。BRG1（也称为SMARCA4）是SWI/SNF染色质重塑复合物的核心成分。在之前的一项研究中，我们报道BRG1表达降低可促进结肠癌细胞的迁移和侵袭，且BRG1表达水平与淋巴转移呈负相关。在本研究中，我们全面分析了BRG1在结直肠癌淋巴管生成中的作用。BRG1低表达肿瘤中的淋巴管比BRG1高表达肿瘤中的更丰富。我们研究了BRG1促进VEGFC转录并在体内外诱导淋巴管生成的过程。我们发现BRG1通过与STAT3结合并调节STAT3激活来控制淋巴管生成。我们还通过临床样本证实了相关机制。总之，我们对BRG1/STAT3/VEGFC在肿瘤相关淋巴管生成中的重要作用的证明，可能会为治疗BRG1功能丧失的癌症发现新的治疗靶点。
