DUOX1 silencing in lung cancer and its association with cancer stem cells
Andrew graduated from Hillsdale College (Hillsdale, MI) in May of 2010 with a B.S. in biochemistry. November 2010, he worked for the University of Michigan department of dermatology under Dr. Gary Fisher, performing research in the photobiology and aging research team. The lab’s primary focus was skin aging and destruction of the extracellular matrix driven by UV-mediated mechanisms.
Andrew is a PhD candidate, he joined CMB in fall of 2012.
The NADPH oxidase homolog DUOX1 is a highly expressed enzyme within the airway epithelium. H2O2 produced via DUOX1 is known to be a potent signaling molecule in host defense and in response to inflammation. It is well established that elevated levels of reactive oxygen species (ROS) is a hallmark of cancer, paradoxically, DUOX1 has been found to be silenced in lung cancer. In order to further investigate the consequences of DUOX1 suppression, stably transfected DUOX1 silenced (shDUOX1) human pulmonary mucoepidermoid carcinoma cells (NCI-H292) were utilized. DUOX1 silencing in vitro was found to be associated with various features of epithelial-mesenchymal transition (EMT) such as: loss of E-cadherin, increased migratory potential and anchorage-independent growth. EMT in lung cancer is often linked with increased resistance to EGFR tyrosine kinase inhibitors, such as erlotinib, as well as the acquisition of cancer stem cell (CSC) phenotypes. Thus, we explored the relationship of DUOX1 silencing and these outcomes. It was found that erlotinib-resistant cells lack DUOX1 expression and congruently shDUOX1 cells display resistance to the drug erlotinib, implying that lack of DUOX1 could potentially drive EMT and the acquisition of CSC phenotypes. Flow cytometric analysis (FACS) was utilized to evaluate several proposed markers of CSCs such as: marker pair CD24Low/CD44High as well as markers CD133 and ALDH1. shDUOX1 cells displayed a greater ratio of CD24Low/CD44High as well as enhanced levels of CD133+ cells as compared to its control. Similar FACS results were observed in erlotinib-resistant cells. The relationship between DUOX1 suppression and lung cancer needs further characterization, although the downregulation of DUOX1 could prove to be an invaluable, novel marker of CSCs.
Swindell WR, et al. (2013) Robust shifts in S100a9 expression with aging: a novel mechanism for chronic inflammation. Sci Rep 3:1215
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Dr. Andrew McKenzie
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