Open AccessHypoxia-inducible factor-dependent ADAM12 expression mediates breast cancer invasion and metastasis
Author(s) -
Ru Wang,
Inês Godet,
Yongkang Yang,
Shaima Salman,
Haiquan Lu,
Yajing Lyu,
Qiaozhu Zuo,
Yufeng Wang,
Yayun Zhu,
Chelsey Chen,
Jianjun He,
Daniele M. Gilkes,
Gregg L. Semenza
Publication year - 2021
Publication title -
proceedings of the national academy of sciences
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2020490118
Subject(s) - metastasis , cancer research , heparin binding egf like growth factor , hypoxia (environmental) , epidermal growth factor , cancer cell , signal transduction , hypoxia inducible factors , breast cancer , biology , epidermal growth factor receptor , growth factor , microbiology and biotechnology , receptor , cancer , medicine , chemistry , gene , organic chemistry , oxygen , biochemistry
Significance Hypoxia (reduced oxygen availability) is a common finding in the tumor microenvironment and plays a critical role in stimulating the metastasis of breast cancer cells from the primary tumor to distant organs, which is closely related to patient mortality. Critical transcriptional responses to reduced O2 availability are mediated by hypoxia-inducible factors (HIFs). In this study, we demonstrate that hypoxia induces HIF-dependent expression of a disintegrin and metalloproteinase 12 (ADAM12), which clips off the extracellular domain of the membrane-bound heparin-binding epidermal growth factor-like growth factor (HB-EGF). The liberated extracellular domain of HB-EGF binds to the epidermal growth factor receptor, triggering a signal transduction pathway that endows breast cancer cells with increased capability for cell migration and invasion, leading to distant metastasis.
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