Novel mechanistic insights into ectodomain shedding of EGFR Ligands Amphiregulin and TGF-α: impact on gastrointestinal cancers driven by secondary bile acids.
Novel mechanistic insights into ectodomain shedding of EGFR Ligands Amphiregulin and TGF-α: impact on gastrointestinal cancers driven by secondary bile acids.
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DOI：
10.1158/0008-5472.can-13-2329
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发表时间：
2014-04-01
期刊：
影响因子：
11.2
通讯作者：
Merchant NB
中科院分区：
文献类型：
--
作者：
Nagathihalli NS;Beesetty Y;Lee W;Washington MK;Chen X;Lockhart AC;Merchant NB
次级胆汁酸（BAs）如脱氧胆酸（DCA）促进了几种胃肠道恶性肿瘤的发展，但它们是如何介导这种作用的尚不清楚。在这项研究中，我们提供了EGFR配体双调节蛋白（AREG）和TGF-α依赖于细胞表面蛋白酶TACE/ADAM-17的外域脱落机制的证据。具体来说，我们发现AREG参与了dca诱导的EGFR和STAT3信号传导、细胞周期进展和人类结直肠癌（CRC）和胰腺导管腺癌（PDAC）的致瘤性。与正常组织相比，CRC和PDAC组织中TACE和AREG均有过表达，TGF-α无过表达。CRC和PDAC细胞暴露于DCA导致Src和TACE在细胞膜上的共定位，导致areg依赖性的EGFR、MAPK和STAT3信号的激活。Src或TACE抑制足以减弱dca诱导的AREG，但不能减弱TGF-α的脱落。我们还研究了胆汁酸转运体TGR5在dca介导的EGFR和STAT3信号传导中的作用。rnai介导的TGR5或AREG的沉默抑制了dca诱导的EGFR、MAPK和STAT3信号，减弱了cyclin D1的表达和细胞周期进程，减弱了dca诱导的CRC或PDAC的致瘤性。总之，我们的研究结果确定了一种areg依赖的信号通路，该通路介导胃肠道癌症中继发性BAs的致癌作用，其靶向性可能增强其治疗反应。
Secondary bile acids (BAs) such as deoxycholic acid (DCA) promote the development of several gastrointestinal malignancies, but how they mediate this effect is unclear. In this study, we offer evidence of a mechanism involving ectodomain shedding of the EGFR ligands amphiregulin (AREG) and TGF-α which rely upon the cell surface protease TACE/ADAM-17. Specifically, we show that AREG participates in DCA-induced EGFR and STAT3 signaling, cell cycle progression and tumorigenicity in human colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC). TACE and AREG, but not TGF-α, were overexpressed in both CRC and PDAC tissues compared to normal tissues. Exposure of CRC and PDAC cells to DCA resulted in co-localization of Src and TACE to the cell membrane, resulting in AREG-dependent activation of EGFR, MAPK and STAT3 signaling. Src or TACE inhibition was sufficient to attenuate DCA-induced AREG, but not TGF-α shedding. We also examined a role for the bile acid transporter TGR5 in DCA-mediated EGFR and STAT3 signaling. RNAi-mediated silencing of TGR5 or AREG inhibited DCA-induced EGFR, MAPK and STAT3 signaling, blunted cyclin D1 expression and cell cycle progression, and attenuated DCA-induced CRC or PDAC tumorigenicity. Together, our findings define an AREG-dependent signaling pathway that mediates the oncogenic effects of secondary BAs in gastrointestinal cancers, the targeting of which may enhance therapeutic responses in their treatment.