Implicación del receptor de dioxina en la transición epitelio-mesénquima, en la pluripotencia y en la reprogramación celular

Abstract

AHR is a highly conserved transcription factor that mediates toxicity and carcinogenesis induced by environmental contaminants. Recent experimental evidence shows that AHR also has a relevant role in cellular homeostasis. Thus, its involvement in cell proliferation and differentiation, in cardiovascular and hepatic development, and in the regulation of TGFβ activity has been observed. In addition, AHR modulates in a manner that depends on the phenotype of the target cell, relevant processes in cancer such as cell adhesion and migration. In this PhD Thesis we have analyzed the role of AHR in the epithelial-mesenchymal transition (EMT), a process that initiates tumor development and is in the origin of local invasion during cancer. To do this, we have produced mouse and human epithelial cell models with different levels of AHR activity; demonstrating that the absence of this protein generates phenotypic changes indicative of EMT, probably due to an increase in TGFβ-dependent signaling. Since non-melanoma skin cancer is the most frequent tumor in humans, we have also studied the contribution of AHR to skin homeostasis and regeneration by isolating and characterizing epidermal stem cells because of their decisive role in the tumor formation. Finally, and since transformation of malignant cells is usually linked to dedifferentiation, we have analyzed the role of AHR in cell reprogramming in both in vitro and in vivo models, demonstrating that its absence favors a more undifferentiated state, and therefore, of worse prognosis.