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A mitochondrial ROS pathway controls matrix metalloproteinase 9 levels and invasive properties in RAS ‐activated cancer cells
Author(s) -
Mori Kazunori,
Uchida Tetsu,
Yoshie Toshihiko,
Mizote Yuko,
Ishikawa Fumihiro,
Katsuyama Masato,
Shibanuma Motoko
Publication year - 2019
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14671
Subject(s) - matrix metalloproteinase , gene knockdown , cancer cell , microbiology and biotechnology , chemistry , downregulation and upregulation , metastasis , cancer research , angiogenesis , biology , reactive oxygen species , cell culture , cancer , biochemistry , gene , genetics
Matrix metalloproteinases ( MMP s) are tissue‐remodeling enzymes involved in the processing of various biological molecules. MMP s also play important roles in cancer metastasis, contributing to angiogenesis, intravasation of tumor cells, and cell migration and invasion. Accordingly, unraveling the signaling pathways controlling MMP activities could shed additional light on cancer biology. Here, we report a molecular axis, comprising the molecular adaptor hydrogen peroxide‐inducible clone‐5 ( HIC ‐5), NADPH oxidase 4 ( NOX 4), and mitochondria‐associated reactive oxygen species (mt ROS ), that regulates MMP 9 expression and may be a target to suppress cancer metastasis. We found that this axis primarily downregulates mt ROS levels which stabilize MMP 9 mRNA . Specifically, HIC ‐5 suppressed the expression of NOX 4, the source of the mt ROS , thereby decreasing mt ROS levels and, consequently, destabilizing MMP 9 mRNA . Interestingly, among six cancer cell lines, only EJ ‐1 and MDA ‐ MB ‐231 cells exhibited upregulation of NOX 4 and MMP 9 expression after sh RNA ‐mediated HIC ‐5 knockdown. In these two cell lines, activating RAS mutations commonly occur, suggesting that the HIC ‐5–mediated suppression of NOX 4 depends on RAS signaling, a hypothesis that was supported experimentally by the introduction of activated RAS into mammary epithelial cells. Notably, HIC ‐5 knockdown promoted lung metastasis of MDA ‐ MB ‐231 cancer cells in mice. The tumor growth of HIC ‐5–silenced MDA ‐ MB ‐231 cells at the primary sites was comparable to that of control cells. Consistently, the invasive properties of the cells, but not their proliferation, were enhanced by the HIC ‐5 knockdown in vitro . We conclude that NOX 4‐mediated mt ROS signaling increases MMP 9 mRNA stability and affects cancer invasiveness but not tumor growth.