ZEB1 induces LOXL2-mediated collagen stabilization and deposition in the extracellular matrix to drive lung cancer invasion and metastasis

Lung cancer is the leading cause of cancer-related deaths, primarily due to distant metastatic disease. Metastatic lung cancer cells can undergo an epithelial-to-mesenchymal transition (EMT) regulated by various transcription factors, including a double-negative feedback loop between the microRNA-20...

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Published in:	Oncogene Vol. 36; no. 14; pp. 1925 - 1938
Main Authors:	Peng, D H, Ungewiss, C, Tong, P, Byers, L A, Wang, J, Canales, J R, Villalobos, P A, Uraoka, N, Mino, B, Behrens, C, Wistuba, I I, Han, R I, Wanna, C A, Fahrenholtz, M, Grande-Allen, K J, Creighton, C J, Gibbons, D L
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 06-04-2017 Nature Publishing Group
Subjects:	13/1 13/105 13/106 13/109 13/51 13/89 14/69 45/15 631/67/1612/1350 631/67/322 631/67/327 82/29 Amino Acid Oxidoreductases - physiology Animals Apoptosis Care and treatment Cell adhesion & migration Cell Biology Cells, Cultured Collagen Collagen - metabolism Cross-linking Development and progression Epithelial-Mesenchymal Transition - genetics Extracellular matrix Extracellular Matrix - genetics Extracellular Matrix - metabolism Female Gene expression Gene Expression Regulation, Neoplastic Genetic aspects Health aspects HEK293 Cells Human Genetics Humans Internal Medicine Isoforms Lung cancer Lung diseases Lung Neoplasms - genetics Lung Neoplasms - pathology Lysyl oxidase Male Malignancy Medicine Medicine & Public Health Mesenchyme Metastases Metastasis Mice miRNA Neoplasm Invasiveness Neoplasm Metastasis Oncology original-article Therapeutic targets Transcription factors Tumor cells Tumors Zinc Finger E-box-Binding Homeobox 1 - physiology
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Summary:	Lung cancer is the leading cause of cancer-related deaths, primarily due to distant metastatic disease. Metastatic lung cancer cells can undergo an epithelial-to-mesenchymal transition (EMT) regulated by various transcription factors, including a double-negative feedback loop between the microRNA-200 (miR-200) family and ZEB1, but the precise mechanisms by which ZEB1-dependent EMT promotes malignancy remain largely undefined. Although the cell-intrinsic effects of EMT are important for tumor progression, the reciprocal dynamic crosstalk between mesenchymal cancer cells and the extracellular matrix (ECM) is equally critical in regulating invasion and metastasis. Investigating the collaborative effect of EMT and ECM in the metastatic process reveals increased collagen deposition in metastatic tumor tissues as a direct consequence of amplified collagen gene expression in ZEB1-activated mesenchymal lung cancer cells. In addition, collagen fibers in metastatic lung tumors exhibit greater linearity and organization as a result of collagen crosslinking by the lysyl oxidase (LOX) family of enzymes. Expression of the LOX and LOXL2 isoforms is directly regulated by miR-200 and ZEB1, respectively, and their upregulation in metastatic tumors and mesenchymal cell lines is coordinated to that of collagen. Functionally, LOXL2, as opposed to LOX, is the principal isoform that crosslinks and stabilizes insoluble collagen deposition in tumor tissues. In turn, focal adhesion formation and FAK/SRC signaling is activated in mesenchymal tumor cells by crosslinked collagen in the ECM. Our study is the first to validate direct regulation of LOX and LOXL2 by the miR-200/ZEB1 axis, defines a novel mechanism driving tumor metastasis, delineates collagen as a prognostic marker, and identifies LOXL2 as a potential therapeutic target against tumor progression.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0950-9232 1476-5594
DOI:	10.1038/onc.2016.358