Department of Anatomy and Cell Biology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
J Invest Dermatol. 2013 Jul;133(7):1863-9. doi: 10.1038/jid.2013.77. Epub 2013 Feb 20.
Cutaneous squamous cell carcinoma (SCC) is the second most common form of cancer in the human population, yet the underlying genetic mechanisms contributing to the disease are not well understood. We recently identified Zmiz1 as a candidate oncogene in nonmelanoma skin cancer through a transposon mutagenesis screen. Here we show that transposon-induced mutations in Zmiz1 drive expression of a truncated transcript that is similar to an alternative endogenous ZMIZ1 transcript found to be overexpressed in human SCCs relative to normal skin. We also describe an original mouse model of invasive keratoacanthoma driven by skin-specific expression of the truncated Zmiz1 transcript. Unlike most mouse models, Zmiz1-induced skin tumors develop rapidly and in the absence of promoting agents such as phorbol esters. In addition, we found that the alternative Zmiz1 isoform has greater protein stability than its full-length counterpart. Finally, we provide evidence that ZMIZ1 is overexpressed in a significant percentage of human breast, ovarian, and colon cancers in addition to human SCCs, suggesting that ZMIZ1 may play a broader role in epithelial cancers.
皮肤鳞状细胞癌（SCC）是人类中第二大常见的癌症类型，但导致该疾病的潜在遗传机制尚不清楚。我们最近通过转座子诱变筛选发现 Zmiz1 是一种非黑色素瘤皮肤癌的候选癌基因。在这里，我们显示转座子诱导的Zmiz1 突变驱动截短转录本的表达，该转录本类似于在人 SCC 中相对于正常皮肤过表达的另一种内源性 ZMIZ1 转录本。我们还描述了一种由截断 Zmiz1 转录本的皮肤特异性表达驱动的侵袭性角化棘皮瘤的原始小鼠模型。与大多数小鼠模型不同，Zmiz1 诱导的皮肤肿瘤快速发展，并且在没有促进剂（如佛波酯）的情况下发展。此外，我们发现替代 Zmiz1 同种型比其全长对应物具有更高的蛋白质稳定性。最后，我们提供的证据表明，ZMIZ1 在除 SCC 之外的人乳腺癌、卵巢癌和结肠癌中大量过表达，这表明 ZMIZ1 可能在上皮癌中发挥更广泛的作用。
