Sequential down-regulation of E-cadherin with squamous cell carcinoma progression:: Loss of E-cadherin via a prostaglandin E2-EP2-dependent posttranslational mechanism
Sequential down-regulation of E-cadherin with squamous cell carcinoma progression:: Loss of E-cadherin via a prostaglandin E2-EP2-dependent posttranslational mechanism
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DOI：
10.1158/0008-5472.can-06-4415
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发表时间：
2007-08-15
期刊：
影响因子：
11.2
通讯作者：
Pentland, Alice P.
中科院分区：
文献类型：
--
作者：
Brouxhon, Sabine;Kyrkanides, Stephanos;Pentland, Alice P.
皮肤癌的发病率正在上升，每年新增病例超过100万例。虽然鳞状细胞癌(SCC)是由紫外线引起的，但其中涉及的机制(S)仍然知之甚少。对上皮细胞的体外研究或检测恶性皮肤病变的报告表明，E-钙粘素介导的细胞-细胞接触的丢失可能是导致SCC的原因之一。其他研究表明，环氧合酶依赖的前列腺素E-2(PGE(2))合成在这一过程中起着关键作用。使用长期紫外线照射的SKH-1小鼠，我们发现随着病变从异型增生发展到鳞状细胞，E-钙粘附素介导的细胞-细胞接触顺序丧失。这种E-钙粘附素的下调在体内急性紫外线暴露后也很明显。在慢性和急性紫外线损伤中，E-钙粘附素水平在表皮PGE2合成增强时下降。在体外，吲哚美辛抑制PGE2的合成，在原代培养的小鼠角质形成细胞(PMK)中靶向删除EP2，或在体内删除EP2受体，均可取消紫外线诱导的E-钙粘附素下调。相反，在PMK中加入PGE2或EP2受体激动剂Butaprost后，E-钙粘素的下降呈剂量和时间依赖性。我们还表明，紫外线照射，通过PGE(2)-EP2信号通路，可能通过下调E-钙粘附素介导的细胞-细胞接触来启动角质形成细胞的肿瘤发生，E-钙粘附素通过动员离开细胞膜，内化到细胞质，并穿梭于溶酶体和蛋白酶体降解途径。进一步了解UV-PGE(2)-EP2如何下调E-钙粘附素，可能会导致治疗皮肤和其他上皮性癌症的新的化学预防策略。
The incidence of skin cancer is on the rise, with over I million new cases yearly. Although it is known that squamous cell cancers (SCC) are caused by UV light, the mechanism(s) involved remains poorly understood. In vitro studies with epithelial cells or reports examining malignant skin lesions suggest that loss of E-cadherin- mediated cell-cell contacts may contribute to SCCs. Other studies show a pivotal role for cyclooxygenase-dependent prostaglandin E-2 (PGE(2)) synthesis in this process. Using chronically UV-irradiated SKH-1 mice, we show a sequential loss of E-cadherin-mediated cell-cell contacts as lesions progress from dysplasia to SCCs. This E-cadherin down-regulation was also evident after acute UV exposure in vivo. In both chronic and acute UV injury, E-cadherin levels declined at a time when epidermal PGE2 synthesis was enhanced. Inhibition of PGE2 synthesis by indomethacin in vitro, targeted deletion of EP2 in primary mouse keratinocyte (PMK) cultures or deletion of the EP2 receptor in vivo abrogated this UV-induced E-cadherin down-regulation. In contrast, addition of PGE2 or the EP2 receptor agonist butaprost to PMK produced a dose- and time-dependent decrease in E-cadherin. We also show that UV irradiation, via the PGE(2)-EP2 signaling pathway, may initiate tumorigenesis in keratinocytes by down-regulating E-cadherin-mediated cell-cell contacts through its mobilization away from the cell membrane, internalization into the cytoplasm, and shuttling through the lysosome and proteasome degradation pathways. Further understanding of how UV-PGE(2)-EP2 down-regulates E-cadherin may lead to novel chemopreventative strategies for the treatment of skin and other epithelial cancers.