Regulation of the Epithelial-Mesenchymal Transition Pathway

Epithelial-to-mesenchymal transition (EMT) is a complex cellular and molecular program during which epithelial cells lose their differentiated characteristics including cell-cell adhesion, planar and apical-basal polarity and lack of motility, and acquire instead mesenchymal features, including motility and invasiveness. EMT occurs in an orchestrated fashion with one of its earliest events involving the disruption of tight junctions that connect epithelial cells. Adherens junction complexes, which contain E-cadherin and β-catenin are also disrupted along with a reorganization of the actin cytoskeleton. EMT is observed in: 1)embryonic implantation and gastrulation and neural crest cell motility 2) wound healing, tissue-regeneration, inflammation and fibrosis 3) the conversion of differentiated epithelial cancer cells into migratory mesenchymal cancer cells which may lead to cancer invasion, systemic cancer cell dissemination and metastasis. EMT is a widely studied phenomenon. Major inducers of EMT that have been identified include TGF-β, Notch, Wnts and growth factors like EGF, IGF, HGF, PDGF and FGF.TGF-β can induce EMT via activation of both smad and non-smad signaling pathways. Smad signaling activates transcription factors like ZEB1/2 and SNAIL1/2 which are known to decrease the expression of E-cadherin, a protein that is indispensible to the formation of adherens junctions. Loss of this protein leads to the disruption of adherens junctions, one of the key markers for epithelial to mesenchymal transition. Non-smad signaling involves Par6 which targets RhoA for degradation to control apical-basal polarity and tight junction dissolution. Wnt is another inducer of EMT. Canonical wnt signaling prevents the targeted degradation of β-catenin, thereby facilitating the nuclear entry of β-catenin where it associates with other transcription factors like TCF/LEF and influences mesenchymal differentiation. Notch signaling deploys two distinct mechanisms that act in synergy to control the expression of Snail-1, a critical regulator of EMT. Notch directly up-regulates Snail-1 expression by recruitment of a transcription complex containing the Notch intracellular domain to the Snail-1 promoter, and second, Notch mediates the hypoxia-induced up-regulation of LOX, which stabilizes the Snail-1 protein.Several RTKs and their associated ligands have also been shown to act as inducers of EMT. The EGF-EGFR receptor ligand pair activate JAK/STAT and Ras/Raf/MEK/ERK signaling pathways which in turn activate transcription factors like Zeb, Snail and Twist that are known to play an important role in EMT. HGF-c-MET, PDGF-PDGFR and FGF-FGFR are other receptor-ligand pairs that are involved in the regulation of E-cadherin, N-cadherin and Claudins - these are junctional proteins that determine cell-cell adhesion. Loss of these proteins is a determining step in the transition from the epithelial to mesenchymal stage. Recently, a number of studies ascribe a role in activating the EMT program to microRNAs like the miR-200 family, miR-205,miR-192 and miR-34a. In most of these cases, regulation of the EMT is coupled to repression of E-cadherin expression. Thus, EMT can be induced by different molecular factors that activate signaling pathways to influence the expression of genes that influence the change from a differentiated epithelial cell to a migratory mesenchymal cell.