Activated monocyte-elicited autophagy orchestrates the metastasis of human hepatocellular carcinoma cells via p65-snail pathway

【作者】 陈东萍； 郑利民；

【Author】 Dong-Ping Chen;Limin Zheng;Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University;

【机构】 Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University；

【摘要】 Both autophagy and tumor microenvironment have been considered crucial for tumor progression. However, little is known about the potential roles of microenvironment in the regulation of tumor-cell autophagy in human hepatocellular carcinoma(HCC). Here, by analyzing HCC clinic samples, we showed that the level of autophagy in tumor cells was higher at the invading edge than that in the tumor nest, and was correlated with both the density of CD68+ monocytes at the same region, and the intra-hepatic metastasis of HCC. Monocytes, either isolated from fresh HCC tissues or activated by tumor cells, served as the critical inflammatory components that efficiently triggered autophagy in tumor cells by producing pro-inflammatory cytokines TNF-a and IL-1β, but not IL-6. Further functional investigations revealed that soluble factors derived from activated monocytes were capable of fostering the migration of liver cancer cells via increased expression of Snail. Such enhancement was markedly attenuated in autophagy-deficient tumor cells due to the hindered activation of p65 and the subsequent impaired expression of Snail. Our results provide novel insights into the fine-tuned regulatory mechanism by which activated monocytes trigger autophagy-dependent metastasis of tumor cells,and thus indicate new strategies for the rational design of autophagy-based anti-cancer therapies.更多还原

【Abstract】 Both autophagy and tumor microenvironment have been considered crucial for tumor progression. However, little is known about the potential roles of microenvironment in the regulation of tumor-cell autophagy in human hepatocellular carcinoma(HCC). Here, by analyzing HCC clinic samples, we showed that the level of autophagy in tumor cells was higher at the invading edge than that in the tumor nest, and was correlated with both the density of CD68+ monocytes at the same region, and the intra-hepatic metastasis of HCC. Monocytes, either isolated from fresh HCC tissues or activated by tumor cells, served as the critical inflammatory components that efficiently triggered autophagy in tumor cells by producing pro-inflammatory cytokines TNF-a and IL-1β, but not IL-6. Further functional investigations revealed that soluble factors derived from activated monocytes were capable of fostering the migration of liver cancer cells via increased expression of Snail. Such enhancement was markedly attenuated in autophagy-deficient tumor cells due to the hindered activation of p65 and the subsequent impaired expression of Snail. Our results provide novel insights into the fine-tuned regulatory mechanism by which activated monocytes trigger autophagy-dependent metastasis of tumor cells,and thus indicate new strategies for the rational design of autophagy-based anti-cancer therapies.更多还原