缺氧诱导因子依赖性 ADAM12 表达介导乳腺癌的侵袭和转移。
Hypoxia-inducible factor-dependent ADAM12 expression mediates breast cancer invasion and metastasis.
机构信息
Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
出版信息
Proc Natl Acad Sci U S A. 2021 May 11;118(19). doi: 10.1073/pnas.2020490118.
Breast cancer patients with increased expression of hypoxia-inducible factors (HIFs) in primary tumor biopsies are at increased risk of metastasis, which is the major cause of breast cancer-related mortality. The mechanisms by which intratumoral hypoxia and HIFs regulate metastasis are not fully elucidated. In this paper, we report that exposure of human breast cancer cells to hypoxia activates epidermal growth factor receptor (EGFR) signaling that is mediated by the HIF-dependent expression of a disintegrin and metalloprotease 12 (ADAM12), which mediates increased ectodomain shedding of heparin-binding EGF-like growth factor, an EGFR ligand, leading to EGFR-dependent phosphorylation of focal adhesion kinase. Inhibition of ADAM12 expression or activity decreased hypoxia-induced breast cancer cell migration and invasion in vitro, and dramatically impaired lung metastasis after orthotopic implantation of MDA-MB-231 human breast cancer cells into the mammary fat pad of immunodeficient mice.
乳腺癌患者原发性肿瘤活检中缺氧诱导因子 (HIFs) 的表达增加，其转移风险增加，这是乳腺癌相关死亡的主要原因。肿瘤内缺氧和 HIFs 调节转移的机制尚未完全阐明。在本文中，我们报告说，人乳腺癌细胞暴露于缺氧会激活表皮生长因子受体 (EGFR) 信号通路，该通路是由 HIF 依赖性表达解整合素和金属蛋白酶 12 (ADAM12) 介导的，ADAM12 介导肝素结合表皮生长因子样生长因子的外显子脱落增加，这是 EGFR 的配体，导致 EGFR 依赖性粘着斑激酶磷酸化。抑制 ADAM12 的表达或活性可减少体外缺氧诱导的乳腺癌细胞迁移和侵袭，并显著损害 MDA-MB-231 人乳腺癌细胞原位植入免疫缺陷小鼠乳腺脂肪垫后肺转移。
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