CHAPTER 1: COMPREHENSIVE LITERATURE REVIEW
1.9. Dissertation Scope
The scope of this dissertation is to characterize the functional and mechanistic
consequences of DUOX1 suppression in lung cancer. Previous studies had highlighted that
DUOX1 expression was silenced through promoter hypermethylation(Luxen, Belinsky and
Knaus), a common mode of transcriptional regulation employed by cancer cells to dampen
tumor suppressor genes. Since DUOX1 expression is coupled to epithelial differentiation,
and has significant roles in normal epithelial maintenance, it seems plausible that
epigenetic removal of DUOX1 could be a product of, or even promote cellular
transformation. Initial studies aim to characterize the loss of DUOX1 in lung epithelial
cells, while monitoring if the acquisition of oncogenic features occurs (e.g. proliferation,
DUOX1, strategies to recover DUOX1 should be employed in attempt to understand if
DUOX1 expression is a direct modulator of cellular phenotypes.
Since DUOX1 enzymatic activity is linked to H2O2 generation, and mediates
epithelial responses through its ability to redox activate the tyrosine kinases Src and
EGFR(Sham et al.; Heppner et al.; Hristova et al.), investigation as to whether DUOX1
loss in lung cancer has direct impacts for their regulation. Indeed, alterations to Src and/or
EGFR regulation, in a redox-dependent or -independent fashion, has potentially dangerous
oncogenic outcomes as Src and EGFR have both been well characterized for their
individual contributions to cancer progression, warranting further examination.
The loss of DUOX1 in cancer, is often paralleled by the loss of its maturation
factor, DUOXA1. This is intuitive, since they share a bidirectional promoter region,
although in some cases, DUOXA1 is expressed in lieu of DUOX1 (e.g. thyroid cancer).
While initial discovery of the DUOXA proteins cataloged them as regulators of the Notch
signaling pathways, they were later deemed maturation factors for DUOX1, and few
reports since then have attempted to characterize the extraneous role of DUOXA1. Despite
the lack of reports, a prominent example of this is the observed interactions between
DUOXA1 and the master tumor suppressor TP53 in breast cancer cells(Ostrakhovitch and
Li), whereas DUOX1 expression is considered to be very low and/or have minimally
defined roles. Unraveling the dynamics between DUOX1 loss in cancer and the potential
acquisition of extraneous DUOXA1 roles may provide insights to novel protein functions.
Lastly, summarizing the biological and clinical importance of the findings put
new avenues of research are discussed, offering the capacity to enhance our knowledge of
the importance of DUOX1 loss in cancer, and how this could be a critical event worthy of
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