Hypoxia-inducible Factor 1 (HIF-1) Promotes Extracellular Matrix Remodeling under Hypoxic Conditions by Inducing P4HA1, P4HA2, and PLOD2 Expression in Fibroblasts (Retracted Article)
Hypoxia-inducible Factor 1 (HIF-1) Promotes Extracellular Matrix Remodeling under Hypoxic Conditions by Inducing P4HA1, P4HA2, and PLOD2 Expression in Fibroblasts (Retracted Article)
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DOI：
10.1074/jbc.m112.442939
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发表时间：
2013-04-12
影响因子：
4.8
通讯作者：
Semenza, Gregg L.
中科院分区：
文献类型：
--
作者：
Gilkes, Daniele M.;Bajpai, Saumendra;Semenza, Gregg L.
细胞外基质（ECM）的组成、组织和顺应性提供了调节组织结构和功能的结构和化学线索。基质成纤维细胞产生的ECM在乳腺癌的侵袭和转移中起着关键作用，而肿瘤内缺氧也会刺激乳腺癌的侵袭和转移。在这里，我们证明，缺氧诱导因子1（HIF-1）是一个关键的调节ECM重塑成纤维细胞在缺氧条件下。HIF-1激活编码胶原脯氨酰（P4 HA 1和P4 HA 2）和赖氨酰（PLOD 2）羟化酶的基因的表达。P4 HA 1和P4 HA 2是胶原沉积所需的，而PLOD 2是ECM硬化和胶原纤维排列所需的。P4 HA 1、P4 HA 2和PLOD 2共同介导响应于缺氧的ECM组成、排列和机械性质的重塑。低氧成纤维细胞对HIF-1依赖性ECM的重塑诱导乳腺癌细胞形态、粘附和运动的改变，从而促进侵袭和转移。
Extracellular matrix (ECM) composition, organization, and compliance provide both architectural and chemical cues that modulate tissue structure and function. ECM produced by stromal fibroblasts plays a key role in breast cancer invasion and metastasis, which are also stimulated by intratumoral hypoxia. Here, we demonstrate that hypoxia-inducible factor 1 (HIF-1) is a critical regulator of ECM remodeling by fibroblasts under hypoxic conditions. HIF-1 activates expression of genes encoding collagen prolyl (P4HA1 and P4HA2) and lysyl (PLOD2) hydroxylases. P4HA1 and P4HA2 are required for collagen deposition, whereas PLOD2 is required for ECM stiffening and collagen fiber alignment. Together P4HA1, P4HA2, and PLOD2 mediate remodeling of ECM composition, alignment, and mechanical properties in response to hypoxia. HIF-1-dependent ECM remodeling by hypoxic fibroblasts induces changes in breast cancer cell morphology, adhesion, and motility that promote invasion and metastasis.