Autophagy-dependent production of secreted factors facilitates oncogenic RAS-driven invasion.
Autophagy-dependent production of secreted factors facilitates oncogenic RAS-driven invasion.
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DOI：
10.1158/2159-8290.cd-13-0841
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发表时间：
2014-04
期刊：
影响因子：
28.2
通讯作者：
Debnath J
中科院分区：
文献类型：
--
作者：
Lock R;Kenific CM;Leidal AM;Salas E;Debnath J
自噬的肿瘤促进功能主要归因于其促进癌细胞存活的能力。然而，新的证据表明自噬在肿瘤发生过程中发挥着其他作用。在这里，我们发现自噬促进致癌 RAS 驱动的入侵。在用致癌 RAS 转化的上皮细胞中，自噬相关基因的耗竭可抑制三维培养中的侵袭，降低细胞运动性，并减少体内肺转移。使用具有自噬能力的细胞的条件培养基进行处理可以挽救自噬缺陷细胞的侵袭能力，表明这些细胞无法分泌 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，这是恢复自噬缺陷细胞的侵袭所必需的。此外，自噬缺陷的细胞表现出 MMP2 和 WNT5A 水平降低。这些结果支持了自噬通过协调产生多种分泌因子来促进癌细胞侵袭的先前未被认识的功能。
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.