Hypoxia and Transforming Growth Factor β Cooperate to Induce Fibulin-5 Expression in Pancreatic Cancer
Hypoxia and Transforming Growth Factor β Cooperate to Induce Fibulin-5 Expression in Pancreatic Cancer
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DOI：
10.1074/jbc.m116.730945
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发表时间：
2016-10-14
影响因子：
4.8
通讯作者：
Brekken, Rolf A.
中科院分区：
文献类型：
--
作者：
Topalovski, Mary;Hagopian, Michelle;Brekken, Rolf A.
细胞外基质（ECM）的沉积是胰腺导管腺癌（PDA）的一个定义性特征，其中ECM信号可以促进癌细胞存活和上皮可塑性程序。然而，ECM信号也可以通过产生细胞毒性水平的活性氧来限制PDA肿瘤生长。例如，由于氧化应激，PDA中基质细胞上的51整合素的过度纤连蛋白刺激导致血管生成减少和肿瘤细胞凋亡增加。纤蛋白-5（Fbln 5）是一种基质细胞蛋白，其阻断纤连蛋白-整联蛋白相互作用，从而直接限制ECM驱动的活性氧产生并支持PDA进展。与正常胰腺组织相比，Fbln 5在PDA间质中表达丰富，然而，刺激Fbln 5在PDA中表达的机制尚不清楚。使用在体外和体内的方法，我们报告说，缺氧触发Fbln 5的表达在TGF-和PI 3 K依赖的方式。发现TGF-受体、PI 3 K或蛋白激酶B（AKT）的药理学抑制可阻断小鼠胚胎成纤维细胞和3 T3成纤维细胞中缺氧诱导的Fbln 5表达。此外，来自小鼠PDA的肿瘤相关成纤维细胞也对TGF-受体和PI 3 K/AKT抑制Fbln 5的抑制有反应。在PDA基因工程小鼠模型中，治疗诱导的缺氧增加了Fbln 5的表达，而TGF-信号传导的药物抑制减少了Fbln 5的表达。这些发现提供了对诱导Fbln 5在PDA中表达的信号传导轴的深入了解，以及阻断其产生的潜在策略。
The deposition of extracellular matrix (ECM) is a defining feature of pancreatic ductal adenocarcinoma (PDA), where ECM signaling can promote cancer cell survival and epithelial plasticity programs. However, ECM signaling can also limit PDA tumor growth by producing cytotoxic levels of reactive oxygen species. For example, excess fibronectin stimulation of 51 integrin on stromal cells in PDA results in reduced angiogenesis and increased tumor cell apoptosis because of oxidative stress. Fibulin-5 (Fbln5) is a matricellular protein that blocks fibronectin-integrin interaction and thus directly limits ECM-driven reactive oxygen species production and supports PDA progression. Compared with normal pancreatic tissue, Fbln5 is expressed abundantly in the stroma of PDA; however, the mechanisms underlying the stimulation of Fbln5 expression in PDA are undefined. Using in vitro and in vivo approaches, we report that hypoxia triggers Fbln5 expression in a TGF-- and PI3K-dependent manner. Pharmacologic inhibition of TGF- receptor, PI3K, or protein kinase B (AKT) was found to block hypoxia-induced Fbln5 expression in mouse embryonic fibroblasts and 3T3 fibroblasts. Moreover, tumor-associated fibroblasts from mouse PDA were also responsive to TGF- receptor and PI3K/AKT inhibition with regard to suppression of Fbln5. In genetically engineered mouse models of PDA, therapy-induced hypoxia elevated Fbln5 expression, whereas pharmacologic inhibition of TGF- signaling reduced Fbln5 expression. These findings offer insight into the signaling axis that induces Fbln5 expression in PDA and a potential strategy to block its production.