Epithelial-mesenchymal transition - activating transcription factors - multifunctional regulators in cancer

Abstract

The process of epithelial to mesenchymal transition (EMT), first noted during embryogenesis, has also been reported in tumor formation and leads to the development of metastatic growth. It is a naturally occurring process that drives the transformation of adhesive, non-mobile epithelial like cells into mobile cells with a mesenchymal phenotype that have ability to migrate to distant anatomical sites. Activating complex network of embryonic signaling pathways, including Wnt, Notch, hedgehog and transforming growth factor-β pathways, lead to the upregulation of EMT activating transcription factors, crucial for normal tissue development and maintenance. However, deregulation of tightly regulated pathways affecting the process of EMT has been recently investigated in various human cancers. Given the critical role of EMT in metastatic tumor formation, better understanding of the mechanistic regulation provides new opportunities for the development of potential therapeutic targets of clinical importance.

Keywords: Cancer; Embryonic signaling pathways; Epithelial-to-mesenchymal transition; Metastatic growth; Transcription factors.

Figure 1

Schematic illustration of embryonic signaling pathways mediating epithelial-to-mesenchymal transition. Wnt, Notch, hedgehog, transforming growth factor β (TGFβ) along with other growth factors of cytokines transduce signal cascades, modulate the expression of epithelial-to-mesenchymal transition (EMT) regulators and allow them to translocate to nucleus. They act as epithelial repressors (EpR) and/or mesenchymal activators (MeA) and bind with E box of promoter regions of epithelial genes and mesenchymal genes respectively. These complexes have an inductive effect on EMT program by repressing epithelial genes and activating mesenchymal genes. IKK: IκB kinase; NF-κB: Nuclear factor kappa B; SMO: Smoothened; TNF-α: Tumor necrosis factor-α; PI3K: Phosphatidylinositol 3 kinase; GSK3β: Glycogen synthase kinase 3β; Fzd: Frizzled.