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c‐Fos separation from Lamin A/C by GDF15 promotes colon cancer invasion and metastasis in inflammatory microenvironment
Author(s) -
Ding Youxiang,
Hao Kun,
Li Zhaohe,
Ma Rong,
Zhou You,
Zhou Zhou,
Wei Mian,
Liao Yan,
Dai Yao,
Yang Yue,
Zhang Xiaobo,
Zhao Li
Publication year - 2020
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.29317
Subject(s) - metastasis , cancer research , colorectal cancer , gene knockdown , cancer , cancer cell , inflammation , in vivo , biology , tumor microenvironment , immunology , cell culture , genetics , microbiology and biotechnology , tumor cells
Inflammatory microenvironment is an important factor for promoting cancer invasion and metastasis, but the underlying molecular mechanisms remain unclear. Here, we mimicked an inflammatory microenvironment both in vitro and in vivo and investigated its effects on the invasion and metastasis of colon cancer. Moreover, colon cancer patient samples were also analyzed statistically. Conditioned medium from the differentiated macrophages induced invasion and migration of colon cancer cells in vitro, which could be reversed by the treatment of a neutralizing anti‐growth differentiation factor 15 (GDF15) antibody, indicating GDF15 involvement in inflammation‐induced invasiveness. Also, we observed similar effects of human recombinant GDF15 on colon cancer cells. Mechanistically, GDF15 activated c‐Fos by separating it from Lamin A/C, increasing transcriptional activity of c‐Fos and regulating EMT gene expressions. However, c‐Fos knockdown using lentivirus shRNA plasmid inhibited GDF15‐triggered invasion and migration in vitro. In vivo, inflammation caused by lipopolysaccharides obviously increased GDF15 secretion, and c‐Fos knockdown reduced the lung metastasis of colon cancer cells in mice model. In addition, c‐Fos expressions in patient samples were found to be associated with colon cancer metastasis and TNM stages. Taken together, GDF15 in inflammatory microenvironment induces colon cancer invasion and metastasis by regulating EMT genes by activating c‐Fos, which might be a potential therapeutic target for metastatic colon cancer.