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Hippo 通路效应物 YAP 和 TAZ 在皮肤黑色素瘤中的促侵袭活性。

Pro-invasive activity of the Hippo pathway effectors YAP and TAZ in cutaneous melanoma.

机构信息

Team "TGF-β and Oncogenesis", Centre de Recherche, Institut Curie, Orsay, France; INSERM U1021, Orsay, France; CNRS UMR 3347, Orsay, France.

Wistar Institute, Philadelphia, Pennsylvania, USA.

出版信息

J Invest Dermatol. 2014 Jan;134(1):123-132. doi: 10.1038/jid.2013.319. Epub 2013 Jul 29.

Abstract

YAP and its paralog protein TAZ are downstream effectors of the Hippo pathway. Both are amplified in many human cancers and promote cell proliferation and epithelial-mesenchymal transition. Little is known about the status of the Hippo pathway in cutaneous melanoma. We profiled Hippo pathway component expression in a panel of human melanoma cell lines and melanocytic lesions, and characterized the capacity of YAP and TAZ to control melanoma cell behavior. YAP and TAZ immuno-staining in human samples revealed mixed cytoplasmic and nuclear staining for both proteins in benign nevi and superficial spreading melanoma. TAZ was expressed at higher levels than YAP1/2 in all cell lines and in those with high invasive potential. Stable YAP or TAZ knockdown dramatically reduced the expression of the classical Hippo target CCN2/connective-tissue growth factor (CTGF), as well as anchorage-independent growth, capacity to invade Matrigel, and ability form lung metastases in mice following tail-vein injection. YAP knockdown also reduced invasion in a model of skin reconstruct. Inversely, YAP overexpression increased melanoma cell invasiveness, associated with increased TEA domain-dependent transcription and CCN2/CTGF expression. Together, these results demonstrate that both YAP and TAZ contribute to the invasive and metastatic capacity of melanoma cells and may represent worthy targets for therapeutic intervention.

摘要

YAP 和其同源蛋白 TAZ 是 Hippo 通路的下游效应因子。两者在许多人类癌症中扩增,并促进细胞增殖和上皮-间充质转化。关于 Hippo 通路在皮肤黑色素瘤中的状态知之甚少。我们对一系列人黑色素瘤细胞系和黑素细胞病变中 Hippo 通路成分的表达进行了分析,并对 YAP 和 TAZ 控制黑色素瘤细胞行为的能力进行了表征。在人类样本中,YAP 和 TAZ 的免疫染色显示两种蛋白在良性痣和浅表扩散性黑色素瘤中均有混合的细胞质和核染色。TAZ 在所有细胞系中以及侵袭潜能高的细胞系中的表达水平均高于 YAP1/2。稳定敲低 YAP 或 TAZ 可显著降低经典 Hippo 靶标 CCN2/结缔组织生长因子(CTGF)的表达,以及非依赖性生长、侵袭 Matrigel 的能力,以及尾静脉注射后在小鼠中形成肺转移的能力。YAP 敲低也降低了皮肤重建模型中的侵袭性。相反,YAP 过表达增加了黑色素瘤细胞的侵袭性,与 TEA 结构域依赖性转录和 CCN2/CTGF 表达增加相关。总之,这些结果表明,YAP 和 TAZ 均有助于黑色素瘤细胞的侵袭和转移能力,可能是治疗干预的有价值靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f138/3938155/518bc67ca742/jid2013319f1.jpg

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