Tenascin-C Downregulates Wnt Inhibitor Dickkopf-1, Promoting Tumorigenesis in a Neuroendocrine Tumor Model
Tenascin-C Downregulates Wnt Inhibitor Dickkopf-1, Promoting Tumorigenesis in a Neuroendocrine Tumor Model
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DOI：
10.1016/j.celrep.2013.09.014
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发表时间：
2013-10-01
期刊：
影响因子：
8.8
通讯作者：
Orend, Gertraud
中科院分区：
文献类型：
--
作者：
Saupe, Falk;Schwenzer, Anja;Orend, Gertraud
细胞外基质分子tenascin-C （TNC）是癌症特异性基质的主要组成部分，TNC的高表达与几种癌症的不良预后有关。为了全面了解TNC在癌症中的功能，我们建立了具有不同TNC表达水平的胰腺β细胞癌变免疫活性转基因小鼠模型，并比较了TNC表达丰富或缺乏的随机神经内分泌肿瘤形成。我们发现TNC促进肿瘤细胞存活、血管生成开关、更多和渗漏的血管、癌症进展和肺微转移。TNC通过阻断肌动蛋白应激纤维形成下调Dickkopf-1 （DKK1）启动子活性，激活Wnt信号，诱导肿瘤和内皮细胞中Wnt靶基因。我们的研究结果表明，DKK1下调是tnc通过提供促血管生成肿瘤微环境促进肿瘤进展的重要机制。
The extracellular matrix molecule tenascin-C (TNC) is a major component of the cancer-specific matrix, and high TNC expression is linked to poor prognosis in several cancers. To provide a comprehensive understanding of TNC's functions in cancer, we established an immune-competent transgenic mouse model of pancreatic beta-cell carcinogenesis with varying levels of TNC expression and compared stochastic neuroendocrine tumor formation in abundance or absence of TNC. We show that TNC promotes tumor cell survival, the angiogenic switch, more and leaky vessels, carcinoma progression, and lung micrometastasis. TNC downregulates Dickkopf-1 (DKK1) promoter activity through the blocking of actin stress fiber formation, activates Wnt signaling, and induces Wnt target genes in tumor and endothelial cells. Our results implicate DKK1 downregulation as an important mechanism underlying TNC-enhanced tumor progression through the provision of a proangiogenic tumor microenvironment.