TGF-beta1 causes epithelial-mesenchymal transition in HaCaT derivatives, but induces expression of COX-2 and migration only in benign, not in malignant keratinocytes
TGF-beta1 causes epithelial-mesenchymal transition in HaCaT derivatives, but induces expression of COX-2 and migration only in benign, not in malignant keratinocytes
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DOI：
10.1016/j.jdermsci.2010.03.002
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发表时间：
2010-05-01
影响因子：
4.6
通讯作者：
Vaheri, Antti
中科院分区：
文献类型：
--
作者：
Rasanen, Kati;Vaheri, Antti
背景：转化生长因子β (tgf - β)通过诱导上皮-间质转化（EMT）作为肿瘤启动子，导致运动表型，使癌细胞能够侵袭和转移。前列腺素介导的癌症相关炎症被认为是良性细胞向恶性细胞转化的关键机制。目的：诱导环氧化酶2 (COX-2)，前列腺素的产生，被认为是tgf - β诱导良性细胞EMT的先决条件。我们使用代表皮肤癌进展的HaCaT衍生物来研究tgf - β 1介导的EMT反应以及COX-2在其中的作用。方法：通过分析细胞增殖、形态及蛋白表达，探讨tgf - β 1对细胞增殖的影响。趋化性和划伤试验用于研究迁移。结果：tgf - β 1使良恶性HaCaT细胞增殖阻滞，使良恶性和低度恶性细胞上皮形态改变为间充质梭形，而转移细胞形态不改变。在所有细胞系中，上皮连接蛋白ZO-1和E-cadherin在tgf - β 1的作用下下调，但间充质标志物未被诱导，提示部分EMT反应。COX-2和迁移仅在良性HaCaT衍生物中诱导。恶性衍生物对tgf - β 1治疗没有诱导COX-2，从而强调炎症在良性细胞EMT反应中的作用。结论：tgf - β 1通过不同的机制诱导EMT和转移，支持这一点，我们发现tgf - β 1诱导COX-2并促进良性细胞的迁移，但不会进一步增强恶性细胞的迁移，表明它们在运动背景下对tgf - β 1的抵抗。(c) 2010年日本皮肤病调查学会。爱思唯尔爱尔兰有限公司出版。版权所有。
Background: Transforming growth factor beta (TGF-beta) acts as a tumor promoter by inducing epithelial-mesenchymal transition (EMT), which leads to a motile phenotype, enabling invasion and metastasis of cancer cells. Cancer-related inflammation, mediated by prostaglandins, has been proposed as a critical mechanism in conversion of benign cells to malignant.Objective: Induction of cyclooxygenase 2 (COX-2), producer of prostaglandins, is thought to be a prerequisite for TGF-beta-induced EMT in benign cells. We used HaCaT derivatives, representative of skin cancer progression, to investigate TGF-beta 1 mediated EMT response, and the role of COX-2 in it.Methods: Effect of TGF-beta 1 was investigated by analyzing cell proliferation, morphology and protein expression. Chemotaxis and scratch-wound assays were used to study migration.Results: TGF-beta 1 caused proliferation arrest of benign and malignant HaCaT cells, and changed the epithelial morphology of benign and low-grade malignant cells, but not metastatic cells, to mesenchymal spindle-shape. Epithelial junction proteins ZO-1 and E-cadherin were downregulated in all cell lines in response to TGF-beta 1, but mesenchymal markers were not induced, suggesting a partial EMT response. COX-2 and migration were induced only in benign HaCaT derivatives. Malignant derivatives did not induce COX-2 in response to TGF-beta 1 treatment, thus emphasizing the role of inflammation in EMT response of benign cells.Conclusions: TGF-beta 1 operates via distinct mechanisms in inducing EMT and metastasis, and supporting this we show that TGF-beta 1 induces COX-2 and promotes the migration of benign cells, but does not further augment the migration of malignant cells, indicating their resistance to TGF-beta 1 in the context of motility. (c) 2010 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.