GSK3β inhibition blocks melanoma cell/host interactions by downregulating N-cadherin expression and decreasing FAK phosphorylation.
GSK3β inhibition blocks melanoma cell/host interactions by downregulating N-cadherin expression and decreasing FAK phosphorylation.
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DOI：
10.1038/jid.2012.237
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发表时间：
2012-12
影响因子：
6.5
通讯作者：
Smalley, Keiran S. M.
中科院分区：
文献类型：
--
作者：
John, Jobin K.;Paraiso, Kim H. T.;Rebecca, Vito W.;Cantini, Liliana P.;Abel, Ethan V.;Pagano, Nicholas;Meggers, Eric;Mathew, Rahel;Krepler, Clemens;Izumi, Victoria;Fang, Bin;Koomen, John M.;Messina, Jane L.;Herlyn, Meenhard;Smalley, Keiran S. M.
本研究探讨糖原合成酶-3β信号转导通路在黑色素瘤发生中的作用。免疫组织化学染色显示GSK3β在12%的原发黑色素瘤和33%的转移性黑色素瘤的侵袭部位有局灶性表达。在划痕实验、三维胶原植入球体实验和改良的Boyden小室实验中，Gsk3抑制剂和Gsk3β的siRNA敲除被发现抑制黑色素瘤细胞的运动行为。在功能上，抑制GSK3β信号被发现在基因和蛋白水平上抑制了N-钙粘素的表达，并与转录因子slug的表达减少有关。药物和基因阻断GSK3β信号可抑制黑色素瘤细胞与内皮细胞和成纤维细胞的黏附，并阻止跨内皮细胞迁移，这一作用可通过强制过表达N-钙粘附素来挽救。Gsk3β信号在侵袭中的进一步作用是通过Gsk3β抑制剂和siRNA敲除来阻断FAK的磷酸化和增加局部粘连的大小。总之，我们已经证明了Gsk3β通过N-钙粘附素和粘着斑激酶调节黑色素瘤细胞的运动和侵袭行为，这是以前没有报道过的作用。这些研究表明，在特定的黑色素瘤亚群中抑制Gsk3β具有潜在的治疗作用。
This study addresses the role of glycogen synthase kinase (GSK)-3β signaling in the tumorigenic behavior of melanoma. Immunohistochemical staining revealed GSK3β to be focally expressed in the invasive portions of 12% and 33% of primary and metastatic melanomas, respectively. GSK3 inhibitors and siRNA knockdown of GSK3β were found to inhibit the motile behavior of melanoma cells in scratch wound, 3D collagen implanted spheroid and modified Boyden chamber assays. Functionally, inhibition of GSK3β signaling was found to suppress N-cadherin expression at the mRNA and protein levels and was associated with decreased expression of the transcription factor Slug. Pharmacological and genetic ablation of GSK3β signaling inhibited the adhesion of melanoma cells to both endothelial cells and fibroblasts and prevented transendothelial migration, an effect rescued by the forced overexpression of N-cadherin. A further role for GSK3β signaling in invasion was suggested by the ability of GSK3β inhibitors and siRNA knockdown to block phosphorylation of FAK and increase the size of focal adhesions. In summary, we have demonstrated a previously unreported role for GSK3β in modulating the motile and invasive behavior of melanoma cells through N-cadherin and FAK. These studies suggest the potential therapeutic utility of inhibiting GSK3β in defined subsets of melanoma.
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影响因子：
8.8
作者：
Davies, M. A.;Stemke-Hale, K.;Tellez, C.;Calderone, T. L.;Deng, W.;Prieto, V. G.;Lazar, A. J. F.;Gershenwald, J. E.;Mills, G. B.
通讯作者：
Mills, G. B.
影响因子：
5.3
作者：
Kobayashi, T;Hino, S;Kikuchi, A
通讯作者：
Kikuchi, A
影响因子：
4
作者：
Koivisto, L;Alavian, K;Larjava, H
通讯作者：
Larjava, H
影响因子：
5.8
作者：
Camilli, Tura C.;Weeraratna, Ashani T.
通讯作者：
Weeraratna, Ashani T.
影响因子：
56.9
作者：
He, TC;Sparks, AB;Kinzler, KW
通讯作者：
Kinzler, KW