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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Loss Of P120 Catenin And Links To Mitotic Alterations, Inflammation, And Skin Cancer
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Loss Of P120 Catenin And Links To Mitotic Alterations, Inflammation, And Skin Cancer

机译：P120连环蛋白的丢失并与有丝分裂改变，炎症和皮肤癌有关

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Tumor formation involves epigenetic modifications and microen-vironmental changes as well as cumulative genetic alterations encompassing somatic mutations, loss of heterozygosity, and an-euploidy. Here, we show that conditional targeting of p 720 catenin in mice leads to progressive development of skin neoplasias associated with intrinsic NF-κB activation. We find that, similarly, squamous cell carcinomas in humans display altered p120 and activated NF-κB. We show that epidermal hyperproliferation arising from p120 loss can be abrogated by IκB kinase 2 inhibitors. Although this underscores the importance of this pathway, the role of NF-κB in hyperproliferation appears rooted in its impact on epidermal microenvironment because as p120-null keratinocytes display a growth-arrested phenotype in culture. We trace this to a mitotic defect, resulting in unstable, binucleated cells in vitro and in vivo. We show that the abnormal mitoses can be ameliorated by inhibiting RhoA, the activity of which is abnormally high. Conversely, we can elicit such mitotic defects in control keratinocytes by elevating RhoA activity. The ability of p120 deficiency to elicit mitotic alterations and chronic inflammatory responses, that together may facilitate the development of genetic instability in vivo, provides insights into why it figures so prominently in skin cancer progression.
机译：肿瘤的形成涉及表观遗传修饰和微环境变化以及累积的遗传变化，包括体细胞突变，杂合性丧失和非整倍性。在这里，我们显示在小鼠中有条件地靶向p 720 catenin会导致与内在NF-κB激活相关的皮肤肿瘤的发展。我们发现，类似地，人类鳞状细胞癌显示出改变的p120和激活的NF-κB。我们显示，IκB激酶2抑制剂可消除p120缺失引起的表皮过度增殖。尽管这强调了该途径的重要性，但由于p120缺失的角质形成细胞在培养物中表现出生长抑制的表型，NF-κB在过度增殖中的作用似乎根源于其对表皮微环境的影响。我们将此归结为有丝分裂缺陷，导致体外和体内不稳定的双核细胞。我们表明，可以通过抑制RhoA来改善异常的有丝分裂，RhoA的活性异常高。相反，我们可以通过提高RhoA活性在对照角质形成细胞中引发这种有丝分裂缺陷。 p120缺乏引起有丝分裂改变和慢性炎症反应的能力，可共同促进体内遗传不稳定性的发展，提供了洞悉其为何在皮肤癌进展中如此重要的见解。

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