驱动依赖_自噬依赖的分泌因子的产生促进致癌RAS驱动的侵袭

摘要

The tumor promoting functions of autophagy are primarily attributed to its ability to promote cancer cell survival. However, emerging evidence suggests that autophagy plays other roles during tumorigenesis. Here, we uncover that autophagy promotes oncogenic RAS-driven invasion. In epithelial cells transformed with oncogenic RAS, depletion of autophagy-related genes suppresses invasion in three-dimensional culture, decreases cell motility, and reduces pulmonary metastases in vivo. Treatment with conditioned media from autophagy-competent cells rescues the invasive capacity of autophagy-deficient cells, indicating these cells fail to secrete factors required for RAS-driven invasion. Reduced autophagy diminishes the secretion of the pro-migratory cytokine IL6, which is necessary to restore invasion of autophagy-deficient cells. Moreover, autophagy-deficient cells exhibit reduced levels of MMP2 and WNT5A. These results support a previously unrecognized function for autophagy in promoting cancer cell invasion via the coordinate production of multiple secreted factors

自噬的促癌功能主要归因于其促进癌细胞存活的能力。然而，新出现的证据表明，自噬在肿瘤发生过程中还扮演着其他角色。在这里，我们发现自噬促进了致癌的RAS驱动的侵袭。在转化了致癌RAS的上皮细胞中，自噬相关基因的缺失抑制了三维培养中的侵袭，降低了细胞的运动性，并减少了体内的肺转移。自噬充足细胞的条件培养基处理挽救了自噬缺陷细胞的侵袭能力，表明这些细胞不能分泌RAS驱动的侵袭所需的因子。自噬减少会减少促迁移细胞因子IL6的分泌，而IL6是恢复自噬缺陷细胞侵袭所必需的。此外，自噬缺陷细胞显示MMP2和Wnt5A水平降低。这些结果支持之前未知的自噬通过多种分泌因子的协调产生促进癌细胞侵袭的功能。

文献来源：Lock R, Kenific CM, Leidal AM, Salas E, Debnath J. Autophagy-dependent production of secreted factors facilitates oncogenic RAS-driven invasion. Cancer Discov. 2014;4(4):466-479. doi:10.1158/2159-8290.CD-13-0841