Periostin Promotes Colorectal Tumorigenesis through Integrin-FAK-Src Pathway-Mediated YAP/TAZ Activation
Periostin Promotes Colorectal Tumorigenesis through Integrin-FAK-Src Pathway-Mediated YAP/TAZ Activation
复制标题
Periostin 通过整合素-FAK-Src 通路介导的 YAP/TAZ 激活促进结直肠肿瘤发生
DOI：
10.1016/j.celrep.2019.12.075
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发表时间：
2020-01-21
期刊：
影响因子：
8.8
通讯作者：
Ouyang, Gaoliang
中科院分区：
文献类型：
--
作者：
Ma, Handong;Wang, Jing;Ouyang, Gaoliang
Periostin是一种多功能细胞外基质蛋白，参与多种炎症性疾病和肿瘤转移；然而，关于骨膜素是否以及如何积极促进炎症相关肿瘤发生的证据仍然难以捉摸。在这里，我们证明骨膜素缺乏显着抑制氧化偶氮甲烷/硫酸葡聚糖钠治疗的小鼠和 Ape(Min/+) 小鼠结直肠癌的发生。此外，骨膜素缺乏会减轻结肠炎的严重程度并减少肿瘤细胞的增殖。从机制上讲，基质成纤维细胞衍生的骨膜素通过整合素介导的由外向内信号传导激活 FAK-Src 激酶，从而激活 YAP/TAZ，随后激活肿瘤细胞中的 IL-6 表达。相反，IL-6 通过激活 STAT3 诱导成纤维细胞中骨膜素表达，最终促进结直肠肿瘤的发展。这些发现提供了骨膜素促进结直肠肿瘤发生的证据，并确定骨膜素和 IL-6 介导的肿瘤-基质相互作用作为治疗结肠炎相关结直肠癌的有希望的靶标。
Periostin is a multifunctional extracellular matrix protein involved in various inflammatory diseases and tumor metastasis; however, evidence regarding whether and how periostin actively contributes to inflammation-associated tumorigenesis remains elusive. Here, we demonstrate that periostin deficiency significantly inhibits the occurrence of colorectal cancer in azoxymethane/dextran sulfate sodium-treated mice and in Ape(Min/+) mice. Moreover, periostin deficiency attenuates the severity of colitis and reduces the proliferation of tumor cells. Mechanistically, stromal fibroblast-derived periostin activates FAK-Src kinases through integrin-mediated outside-in signaling, which results in the activation of YAP/TAZ and, subsequently, IL-6 expression in tumor cells. Conversely, IL-6 induces periostin expression in fibroblasts by activating STAT3, which ultimately facilitates colorectal tumor development. These findings provide the evidence that periostin promotes colorectal tumorigenesis, and identify periostin- and IL-6-mediated tumor-stroma interaction as a promising target for treating colitis-associated colorectal cancer.