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Inactivation of the serine protease HTRA1 inhibits tumor growth by deregulating angiogenesis.
Oncogene ( IF 8 ) Pub Date : 2018-Aug-01 , DOI: 10.1038/s41388-018-0258-4
Ralph Klose , M. Gordian Adam , Eva-Maria Weis , Iris Moll , Joycelyn Wüstehube-Lausch , Fabian Tetzlaff , Chio Oka , Michael Ehrmann , Andreas Fischer

The serine protease HTRA1 is involved in several vascular diseases and its expression is often deregulated in cancer. We aimed at identifying how HTRA1 in the vasculature affects tumor growth. Here we report that silencing of HTRA1 in cultured endothelial cells increased migration rate and tube formation, whereas forced HTRA1 expression impaired sprouting angiogenesis. Mechanistically, endothelial HTRA1 expression enhanced Delta/Notch signaling by reducing the amount of the weak Notch ligand JAG1. HTRA1 physically interacted with JAG1 and cleaved it within the intracellular domain, leading to protein degradation. Expression of a constitutive active Notch1 prevented the hypersprouting phenotype upon silencing of HTRA1. In HtrA1-deficient mice, endothelial Notch signaling was diminished and isolated endothelial cells had increased expression of VEGF receptor-2. Growth of syngeneic tumors was strongly impaired in HtrA1-/- mice. The tumor vasculature was much denser in HtrA1-/- mice and less covered with mural cells. This chaotic and immature vascular network was poorly functional as indicated by large hypoxic tumor areas and low tumor cell proliferation rates. In summary, inhibition of HTRA1 in the tumor stroma impaired tumor progression by deregulating angiogenesis.

中文翻译:

丝氨酸蛋白酶HTRA1的失活通过调节血管生成来抑制肿瘤的生长。

丝氨酸蛋白酶HTRA1与多种血管疾病有关,其表达在癌症中常常被失调。我们旨在确定脉管系统中的HTRA1如何影响肿瘤的生长。在这里我们报道,在培养的内皮细胞中沉默HTRA1会增加迁移速率和管形成,而强迫的HTRA1表达会损害发芽血管新生。从机制上讲,内皮细胞HTRA1的表达通过减少弱的Notch配体JAG1的数量来增强Delta / Notch信号传导。HTRA1与JAG1发生物理相互作用,并在细胞内结构域内裂解,从而导致蛋白质降解。组成型活性Notch1的表达可防止HTRA1沉默后的过度发芽表型。在缺乏HtrA1的小鼠中,内皮Notch信号减少,分离的内皮细胞增加VEGF受体2的表达。HtrA1严重损害了同基因肿瘤的生长-/-老鼠。在HtrA1 -/-小鼠中,肿瘤脉管系统密度更高,而壁膜细胞覆盖率则更低。如大的缺氧肿瘤区域和低的肿瘤细胞增殖率所表明的,该混乱且未成熟的血管网络功能差。总之,在肿瘤基质中抑制HTRA1通过使血管生成失调而损害了肿瘤的进展。
更新日期:2018-05-01
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