Verhaegen Monique E, Mangelberger Doris, Harms Paul W, Vozheiko Tracy D, Weick Jack W, Wilbert Dawn M, Saunders Thomas L, Ermilov Alexandre N, Bichakjian Christopher K, Johnson Timothy M, Imperiale Michael J, Dlugosz Andrzej A
Department of Dermatology, University of Michigan, Ann Arbor, MI 48109.
Department of Pathology, University of Michigan, Ann Arbor, MI 48109.
J Invest Dermatol. 2015 May;135(5):1415-1424. doi: 10.1038/jid.2014.446. Epub 2014 Oct 14.
Merkel cell carcinoma (MCC) is a rare and deadly neuroendocrine skin tumor frequently associated with clonal integration of a polyomavirus, Merkel cell polyomavirus (MCPyV), and MCC tumor cells express putative polyomavirus oncoprotein small T antigen (sTAg) and truncated large T antigen. Here, we show robust transforming activity of sTAg in vivo in a panel of transgenic mouse models. Epithelia of preterm sTAg-expressing embryos exhibited hyperplasia, impaired differentiation, increased proliferation, and apoptosis, and activation of a DNA damage response. Epithelial transformation did not require sTAg interaction with the protein phosphatase 2A protein complex, a tumor suppressor in some other polyomavirus transformation models, but was strictly dependent on a recently described sTAg domain that binds Fbxw7, the substrate-binding component of the Skp1/Cullin1/F-box protein ubiquitin ligase complex. Postnatal induction of sTAg using a Cre-inducible transgene also led to epithelial transformation with development of lesions resembling squamous cell carcinoma in situ and elevated expression of Fbxw7 target proteins. Our data establish that expression of MCPyV sTAg alone is sufficient for rapid neoplastic transformation in vivo, implicating sTAg as an oncogenic driver in MCC and perhaps other human malignancies. Moreover, the loss of transforming activity following mutation of the sTAg Fbxw7 binding domain identifies this domain as crucial for in vivo transformation.
默克尔细胞癌（MCC）是一种罕见且致命的神经内分泌皮肤肿瘤，常与多瘤病毒——默克尔细胞多瘤病毒（MCPyV）的克隆整合相关，MCC肿瘤细胞表达假定的多瘤病毒癌蛋白小T抗原（sTAg）和截短的大T抗原。在此，我们在一组转基因小鼠模型中展示了sTAg在体内强大的转化活性。表达sTAg的早产胚胎上皮表现出增生、分化受损、增殖增加和凋亡，以及DNA损伤反应的激活。上皮转化并不需要sTAg与蛋白磷酸酶2A蛋白复合物相互作用，而在其他一些多瘤病毒转化模型中，该复合物是一种肿瘤抑制因子，但它严格依赖于最近描述的一个与Fbxw7结合的sTAg结构域，Fbxw7是Skp1/Cullin1/F盒蛋白泛素连接酶复合物的底物结合成分。使用Cre诱导型转基因在出生后诱导sTAg表达也导致上皮转化，并出现原位鳞状细胞癌样病变以及Fbxw7靶蛋白表达升高。我们的数据表明，单独表达MCPyV sTAg足以在体内快速发生肿瘤转化，这表明sTAg是MCC以及可能其他人类恶性肿瘤中的致癌驱动因素。此外，sTAg的Fbxw7结合结构域突变后转化活性丧失，表明该结构域对体内转化至关重要。
