Ion channel TRPV1-dependent activation of PTP1B suppresses EGFR-associated intestinal tumorigenesis
Ion channel TRPV1-dependent activation of PTP1B suppresses EGFR-associated intestinal tumorigenesis
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DOI：
10.1172/jci72340
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发表时间：
2014-09-01
影响因子：
15.9
通讯作者：
Raz, Eyal
中科院分区：
文献类型：
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作者：
de Jong, Petrus R.;Takahashi, Naoki;Raz, Eyal
肠上皮细胞具有很高的周转率，调节再生的途径的失调可导致肿瘤的发展;然而，肠上皮细胞中致癌事件的负调节因子尚未完全了解。在这里，我们确定了表皮生长因子受体（EGFR），一个已知的介质的增殖，和瞬时受体电位阳离子通道，亚家族V，成员1（TRPV 1），在肠上皮细胞（IEC）之间的反馈回路。我们发现TRPV 1由IEC表达，并在EGFR刺激后被内在激活。随后，TRPV 1激活通过激活Ca 2 +/钙蛋白酶和导致的蛋白酪氨酸磷酸酶1B（PTP 1B）的激活抑制EGFR诱导的上皮细胞增殖。在多发性肠肿瘤小鼠模型（Apc（Min/+）小鼠）中，TRPV 1缺陷增加了腺瘤形成，用EGFR激酶抑制剂治疗这些动物逆转了促肿瘤发生表型，支持IEC中TRPV 1和EGFR信号传导之间的功能关联。TRPV 1激动剂的给药抑制了Apc（Min/+）小鼠的肠道肿瘤发生，与环氧合酶-2（考克斯-2）抑制剂相似，也与之联合，这表明靶向TRPV 1和考克斯-2具有作为肿瘤预防治疗方法的潜力。我们的研究结果表明TRPV 1通过激活PTP 1B和随后的抑制肠道肿瘤发生，作为肠上皮细胞中生长因子信号传导的调节剂。
The intestinal epithelium has a high rate of turnover, and dysregulation of pathways that regulate regeneration can lead to tumor development; however, the negative regulators of oncogenic events in the intestinal epithelium are not fully understood. Here we identified a feedback loop between the epidermal growth factor receptor (EGFR), a known mediator of proliferation, and the transient receptor potential cation channel, subfamily V, member 1 (TRPV1), in intestinal epithelial cells (IECs). We found that TRPV1 was expressed by IECs and was intrinsically activated upon EGFR stimulation. Subsequently, TRPV1 activation inhibited EGFR-induced epithelial cell proliferation via activation of Ca2+/calpain and resulting activation of protein tyrosine phosphatase 1B (PTP1B). In a murine model of multiple intestinal neoplasia (Apc(Min/+) mice), TRPV1 deficiency increased adenoma formation, and treatment of these animals with an EGFR kinase inhibitor reversed protumorigenic phenotypes, supporting a functional association between TRPV1 and EGFR signaling in IECs. Administration of a TRPV1 agonist suppressed intestinal tumorigenesis in Apc(Min/+) mice, similar to - as well as in conjunction with - a cyclooxygenase-2 (COX-2) inhibitor, which suggests that targeting both TRPV1 and COX-2 has potential as a therapeutic approach for tumor prevention. Our findings implicate TRPV1 as a regulator of growth factor signaling in the intestinal epithelium through activation of PTP1B and subsequent suppression of intestinal tumorigenesis.