Ets1 Induces Dysplastic Changes When Expressed in Terminally-Differentiating Squamous Epidermal Cells

Abstract

BackgroundEts1 is an oncogene that functions as a transcription factor and regulates the activity of many genes potentially important for tumor initiation and progression. Interestingly, the Ets1 oncogene is over-expressed in many human squamous cell cancers and over-expression is highly correlated with invasion and metastasis. Thus, Ets1 is believed to mainly play a role in later stages of the oncogenic process, but not early events.Methodology/Principal FindingsTo better define the role of Ets1 in squamous cell carcinogenesis, we generated a transgenic mouse model in which expression of the Ets1 oncogene could be temporally and spatially regulated. Upon Ets1 induction in differentiating cells of stratified squamous epithelium, these mice exhibited dramatic changes in epithelial organization including increased proliferation and blocked terminal differentiation. The phenotype was completely reversed when Ets1 expression was suppressed. In mice where Ets1 expression was re-induced at a later age, the phenotype was more localized and the lesions that developed were more invasive. Many potential Ets1 targets were upregulated in the skin of these mice with the most dramatic being the metalloprotease MMP13, which we demonstrate to be a direct transcriptional target of Ets1.Conclusions/SignificanceCollectively, our data reveal that upregulation of Ets1 can be an early event that promotes pre-neoplastic changes in epidermal tissues via its regulation of key genes driving growth and invasion. Thus, the Ets1 oncogene may be important for oncogenic processes in both early and late stages of tumor development.

Ets1 blocks terminal differentiation of keratinocytes and induces expression of matrix metalloproteases and innate immune mediators

“…In normal tissues, Ets1 is expressed only in the basal layer of stratified squamous epithelium (Nagarajan et al, 2009). However, in a large fraction of SCC tumors, Ets1 is highly expressed within the malignant keratinocytes, and its levels directly correlate with the invasive and metastatic potential of the tumor (Bai et al, 2009;Endo et al, 2006;Keehn et al, 2004;Pande et al, 1999;Saeki et al, 2000;Vairaktaris et al, 2007).…”

“…However, in a large fraction of SCC tumors, Ets1 is highly expressed within the malignant keratinocytes, and its levels directly correlate with the invasive and metastatic potential of the tumor (Bai et al, 2009;Endo et al, 2006;Keehn et al, 2004;Pande et al, 1999;Saeki et al, 2000;Vairaktaris et al, 2007). Tumors that express high levels of Ets1 typically also express high levels of several matrix metalloprotease (Mmp) genes (Dittmer, 2003;Hahne et al, 2008;Lincoln and Bove, 2005) and Ets1 has been shown to directly regulate expression of multiple Mmp genes (Baillat et al, 2006;Nagarajan et al, 2009;Ozaki et al, 2000;Reisdorff et al, 2002;Wei et al, 2009;Westermarck et al, 1997). Yet, it has been unclear whether the sole oncogenic role of Ets1 is upregulation of Mmp expression or whether this protein also promotes squamous cell carcinoma development by affecting other pathways.…”

“…Yet, it has been unclear whether the sole oncogenic role of Ets1 is upregulation of Mmp expression or whether this protein also promotes squamous cell carcinoma development by affecting other pathways. To address this question, we developed an inducible transgenic mouse model in which Ets1 can be induced in differentiating squamous keratinocytes (Nagarajan et al, 2009). Our studies indicate that induction of Ets1 in adult mice leads to severe dysplastic lesions accompanied by high levels of several Mmp enzymes, most notably Mmp13.…”

“…We have previously described a bi-transgenic (designated BT) mouse model system in which we can inducibly express the transcription factor Ets1 in a tightly regulated, tissue-and differentiation-specific pattern (Nagarajan et al, 2009). In this system, one transgenic line (the responder transgenic) contains an N-terminal hemagglutinin (HA)-tagged mouse Ets1 transgene, cloned downstream of the doxycycline-regulated pTight promoter.…”

“…a Tet-off system). Induction of Ets1 in adult mice leads to severe dysplastic lesions of the skin, reminiscent of squamous cell carcinoma-in-situ (Nagarajan et al, 2009).…”