Previous results in studies demonstrate that Nrf2activation is a promising strategy for skin cancer prevention as it activatescompounds known to suppress tumorigenesis through their anti-inflammatory andchemopreventive activities. It has been proved that Nrf2 activation does notaffect keratinocyte proliferation whereas throughout this project, wedemonstrate that Nrf2 activation does affect SCC proliferation19.
Whatis known about the role of Nrf2 in SCC initiation is that it alters glutathione,amino acid and purine metabolic pathways. Its activation enhances expression ofenzymes involved in glutathione and NADPH production in keratinocytes. The still unansweredquestion is to understand the change from a regular stem cell which is self-renewingand differentiating while keeping tissue homeostasis to the situation where it’sgoing to be transformed and be in a position where the cell renewing processhas increased while the differentiation is being repressed, and what triggers that change.
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Precedent data to discovermolecular markers unique to SCC TICs (tumor initiating cells) has shown that transcriptionfactors Sox2 and Pitx1 are the most consistently molecules expressed in all TIC populations with expressionrepressed in normal skin epithelial stem as well as in their differentiatingprogeny21,22,23. These two transcription factors are only expressedin the nuclei of tumor propagating cells in hSCC grafts and the ones with self-renewalcapacity, while they are not expressing the differentiation of SCCs. They canbe found in mouse and human SCCs, while they are not detectable in normal skinepithelial cells22. Studies have indicatedthat Sox2 and Pitx1 are essential to maintain self-renewal and restrictdifferentiation on those cells. The expansion of tumour initiating SCC cellsalong the stroma interface, is known to be dependent on SOX2 expressioncritical for tumor initiation and growth22.
Previous Chip-seq (chromatinimmunoprecipitation sequencing) analysis done by our group has demonstratedthat transcription factors Sox2 and Pitx1 directly bindto regulatory regions of ROS scavenging genes (Figure 3).