Epithelial to Mesenchymal Transition
Transition of epithelial cells into motile mesenchymal cells known as epithelial to mesenchymal transition (EMT). EMT is a crucial process for some events like wound healing, development and cancer progression. EMT is also essential process for migration and cell fate.
Regulation or dysregulation of cell proliferation, motility and migration is not monopolized by one signaling pathway or just one molecule. In this context, crosstalk between signaling pathways becomes important.
Within the scope of this thesis, we investigated downstream effects of deregulated EGFR and WNT pathways, one of which is EMT.
Epithelial to Mesenchymal Transition Transcription Factors
Key transcription factors during mesenchymal transition are SNAIL, SLUG, ZEB1 and TWIST. They control expression of each other. They also co-regulate target genes. As a result of transcriptional profile change, epithelial cells gain some mesenchymal properties while losing some of their epithelial characteristics.
SNAIL which is a zinc finger transcription factor suppresses E-cadherin (Epithelial cadherin). Accumulation of SNAIL in nucleus is a key process to promote EMT. SNAIL directly binds the promoter region of E-cadherin and this binding represses the expression of E-cadherin. Cells which have repressed E-cadherin will eventually go into mesenchymal transition. This transcription factor also plays role in wound healing and organogenesis. Like other EMT markers, SNAIL associated with metastasis especially in breast carcinoma MDA-MB-231 cells. Overexpression of SNAIL is shown to increase metastasis in colorectal cancer.
SLUG, a member of SNAIL family, is another zinc finger transcription factor that is involved in EMT. SLUG also participates in organogenesis and wound healing. As is the case with SNAIL, SLUG also represses E-cadherin expression. It has been shown that SLUG expression is increased in colon cancer. It is also reported that SLUG expression is related with metastasis in colon cancer and expression of SLUG affects the survival of colon cancer patients.
Zinc finger E-box binding homeobox1 (ZEB1) also known as TCF8 is a transcription factor which promotes migration and invasion by inducing EMT. ZEB1, like SNAIL, is also regulated by signaling pathways like WNT, TGF-β and NFκB. By binding E-box region on DNA, ZEB1 can regulate the target genes. For example, E-box is found in the promoter region of the E-cadherin. Therefore, E-cadherin can be regulated by ZEB1 through binding the E-box region. Downregulation of E-cadherin through ZEB1 and E-box interaction eventually leads to EMT induction. It was shown that overexpression of ZEB1 induce EMT in colon cancer. Knocking down of ZEB1 inhibits epithelial-mesenchymal transition in breast, lung and colon cancer.
Another transcription factor that related to EMT is TWIST1. It belongs to a helix-loop-helix protein family. By regulating EMT, TWIST1 contributes to metastasis. TWIST1 is also associated with poor prognosis in cancer. TWIST1 can also repressing E-cadherin.
EMT Cell Surface Protein
Cadherins are cell surface proteins that play roles in cell movement and tissue morphogenesis. They are essential for adhesion. They are divided into three subfamilies as E (epithelial) -N (neural) and P (placental) cadherins. E-cadherin mediates epithelial cell to cell adhesion. N-cadherin is subfamily of cadherins and known as EMT marker. During the EMT process, N- cadherin expression is increased, and this increase leads to alters cell adhesion. Through homotypic N-cadherin interactions, cells tend to acquire more mesenchymal features and these interactions lead to migration and invasion. Normally, N-cadherin is not expressed in epithelial cells however it may be expressed in some carcinomas.
It has been shown that if there is a transition of expression level from E-cadherin to N-cadherin, it promotes migration and also invasion in cancer cells. This is because of the affected cell polarity since expression level of E-cadherin is decreasing and N-cadherin is increasing. Higher level of N-cadherin expression is also associated with lower survival rate in colon cancer patients. This gives rise to N-cadherin to be used as prognostic marker on colon cancer.
Zonula occludens 1(ZO-1) known as tight junction protein and in normal epithelial cells, it is in a complex, which located at cell-to-cell adhesion membrane. When cell goes into EMT, ZO-1 is separated from complex and goes into cytoplasm and nucleus. The amount of disassociated ZO-1 from complex and translocation of it to nucleus depends on the grade of migration and differentiation. ZO-1 has been linked to EMT in colorectal cancer. In invasive cells, ZO-1 is required for matrix degradation.