Overexpression of the cellular DEK protein promotes epithelial transformation in vitro and in vivo.
Overexpression of the cellular DEK protein promotes epithelial transformation in vitro and in vivo.
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DOI：
10.1158/0008-5472.can-08-2304
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发表时间：
2009-03-01
期刊：
影响因子：
11.2
通讯作者：
Wells SI
中科院分区：
文献类型：
--
作者：
Wise-Draper TM;Mintz-Cole RA;Morris TA;Simpson DS;Wikenheiser-Brokamp KA;Currier MA;Cripe TP;Grosveld GC;Wells SI
人类dek基因的高水平表达与许多人类恶性肿瘤有关。细胞内DEK的功能已在体外被描述，包括DNA超卷曲、DNA复制、RNA剪接和转录。我们已经证明DEK还可以抑制细胞的衰老、凋亡和分化，从而在单层和器官型上皮瓣模型中促进细胞的生长和存活。这些功能可能会导致癌症，但将DEK作为癌基因的直接证据仍然难以捉摸。在这里，我们证明了与肿瘤发生的早期作用一致，在DEK基因敲除小鼠中，在经典化学致癌模型中小鼠乳头状瘤的形成被减少。此外，HPVE6/E7、HRAS和DEK在软琼脂中角质形成细胞的转化和异种移植的建立中起协同作用，因此DEK也参与了肿瘤的后期促进。最后，通过shRNA表达的腺病毒耗尽导致了体内外人类肿瘤细胞的死亡，但对分化的上皮细胞没有明显的影响。综上所述，我们的数据揭示了致癌的DEK活性可能源于其在人类恶性肿瘤中的频繁上调，并提示靶向抑制DEK可能成为癌症治疗的一种战略方法。
High levels of expression of the human DEK gene have been correlated with numerous human malignancies. Intracellular DEK functions have been described in vitro and include DNA supercoiling, DNA replication, RNA splicing, and transcription. We have demonstrated DEK also suppresses cellular senescence, apoptosis and differentiation, thus promoting cell growth and survival in monolayer and organotypic epithelial raft models. Such functions are likely to contribute to cancer, but direct evidence to implicate DEK as an oncogene has remained elusive. Here we show that in line with an early role in tumorigenesis, murine papilloma formation in a classical chemical carcinogenesis model was reduced in DEK knockout mice. Additionally, HPV E6/E7, hRas and DEK cooperated in the transformation of keratinocytes in soft agar and xenograft establishment, thus also implicating DEK in tumor promotion at later stages. Finally, adenoviral DEK depletion via shRNA expression resulted in cell death in human tumor cells in vitro and in vivo, but did not significantly affect differentiated epithelial cells. Taken together, our data uncover oncogenic DEK activities as postulated from its frequent upregulation in human malignancies, and suggest that the targeted suppression of DEK may become a strategic approach to the treatment of cancer.