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DUOX1 Silencing in Lung Cancer Promotes Epithelial‐to‐Mesenchymal Transition and Increased Drug Resistance
Author(s) -
Little Andrew,
Hristova Milena,
Vliet Albert
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.863.19
Subject(s) - erlotinib , epithelial–mesenchymal transition , gene silencing , cancer research , biology , lung cancer , cancer , small hairpin rna , cancer stem cell , medicine , cell culture , pathology , epidermal growth factor receptor , metastasis , genetics , gene , biochemistry , gene knockdown
Rationale and Objective: Dual oxidase 1 (DUOX1) is an H 2 O 2 ‐generating enzyme within the airway epithelium with functional roles in innate host defense and epithelial homeostasis. DUOX1 is suppressed in lung cancers by epigenetic silencing, although its functional importance is unknown. We used RNAi approaches to investigate the impact of DUOX1 silencing on various molecular and functional features of lung cancer. Results: Stable transfection of DUOX1‐targeted shRNA in the lung cancer cell line H292 (H292‐shDUOX1) was found to result in loss of functional and molecular epithelial characteristics and increased mesenchymal features, suggesting the occurrence of epithelial‐to‐mesenchymal transition (EMT). EMT in lung cancer has been associated with enhanced resistance to EGFR tyrosine kinase inhibitors (TKI) and with enrichment of cancer stem cell (CSC) populations. Indeed, H292‐shDUOX1 cells are resistant to the EGFR TKI erlotinib and display elevated expression of CSC markers such as CD24 high /CD44 low, CD133 and ALDH1. Furthermore, induction of EMT by acquired erlotinib resistance in H292 cells or sorting of EMT subpopulations (based on CD24 low /CD44 high ) demonstrated dramatically reduced DUOX1 expression, further establishing the close association between loss of DUOX1 and EMT. Conclusions Our findings indicate that DUOX1 silencing in lung epithelial cells promotes features of EMT, and may thereby be strongly associated with invasive and metastatic lung cancer, and potentially also contribute to other EMT‐related lung pathologies such as chronic obstructive pulmonary disease (COPD). Funding Source: NIH 5R01HL085646, UVM College of Medicine