COUP-TFII regulates metastasis of colorectal adenocarcinoma cells by modulating Snail1

Metastasis distinguishes malignant tumour cells from benign and normal cells and is the main cause of short survival and high mortality for cancer patients (Mareel, 1984). Metastasis is a complex process that includes invasion, survival and arrest in the bloodstream, and metastatic colonisation by cancer cells (Steeg, 2006). The first steps of metastasis are breaking away from neighbouring cells and the extracellular matrix, proteolytic degradation of surrounding tissue, and motility that propels a tumour cell through tissue. Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) is a key molecule in the development of cancers including cancer of the breast, lung, and prostate, and adrenal cancer. Chicken ovalbumin upstream promoter-transcription factor II is involved in the regulation of cell migration in cancer invasion and metastasis in lung and breast cancers. Chicken ovalbumin upstream promoter-transcription factor II is a member of the nuclear hormone-receptor superfamily (Sugiyama et al, 2000). It is highly expressed in the mesenchyme and is critical for mouse development of heart, skeletal muscle, and vein (Pereira et al, 1999; Lee et al, 2004; You et al, 2005; Lee et al, 2012). Recently, COUP-TFII was found to be expressed in many tumour cell lines (Kieback et al, 1993) including from human endometrial, lung, pancreatic, and breast cancers, and from adrenal tumours (Kieback et al, 1996; Wu et al, 1997; Shibata et al, 1998; Prahalad et al, 2010; Qin et al, 2010). Chicken ovalbumin upstream promoter-transcription factor II is not expressed in terminally differentiated epithelial cells but is important in mesenchymal-endothelial interactions, angiogenesis, and tumour growth and metastasis by inhibition of TGF-β-induced growth barrier (Qin et al, 2010) and negative regulating transactivation of androgen receptor (Song et al, 2012). In adult xenografted mice, COUP-TFII compromises neoangiogenesis and suppresses tumour growth (Qin et al, 2010). Chicken ovalbumin upstream promoter-transcription factor II functions as a transcription factor by promoting or repressing tissue-specific gene expression (De Martino et al, 2004; Litchfield and Klinge, 2012). It decreases expression of aldehyde dehydrogenase 2 family (ALDH2), apolipoprotein A-I (APOA1), apolipoprotein A-IV (APOA4), GATA binding protein 6 (GATA6), and haemoglobin, epsilon 1 (HBE1). However, COUP-TFII increases expression of angiopoietin 1 (ANGPT1), HNF1 homeobox A (HNF1A), VEGFR2; kinase insert domain receptor (a type III receptor tyrosine kinase; HDR), and Hepatocyte nuclear factor 4, alpha (HNF4A). However, the roles and mechanisms of action of COUP-TFII in colon cancer development remain largely unknown. Snail1 is a member of the Snail family of transcription factors that induces epithelial-to-mesenchymal transitions and accelerates tumour metastasis via both enhanced invasive ability and regulation of E-cadherin and immunosuppression (Cano et al, 2000; Li et al, 2007; Kudo-Saito et al, 2009). Xu et al (2013) reported that Snail1 regulates hepatocellular carcinoma malignancy by binding to and repressing the promoter of the Cezanne2 gene. Snail1 facilitates breast cancer metastasis through stabilisation by the collagen receptor discoidin domain receptor 2 (Zhang et al, 2013). Adult mice lacking COUP-TFII are largely normal without visible defects (Pereira et al, 1999). Therefore, in this study, we employed COUP-TFII knockout mice as a colon cancer model. We found that both COUP-TFII and Snail1 expression are enhanced in human colon cancer tissues. This aberrant COUP-TFII overexpression correlated with survival of colon cancer patients, suggesting that COUP-TFII function in colon cancer development. Overexpression of COUP-TFII promoted colon cancer cell metastasis by enhancing Snail1 expression.