Epiregulin in non-small cell lung carcinoma
Alison K. Bauer1, Kalpana Velmurugan1, Meredith Tennis2, and Daniel Merrick3
Departments of Environmental and Occupational Health,1 Pulmonary Medicine,2 and Pathology3, University of Colorado, Denver
Lung cancer is the leading cause of cancer deaths among all types of cancer. The most prevalent type of lung cancer is non-small cell lung carcinoma (NSCLC) that accounts for ~85% of lung cancer and has two primary subtypes (adenocarcinoma (ADC) and squamous cell carcinoma (SCC)). Unfortunately, few early biomarkers as well as effective therapies exist, hence the need for novel targets in lung cancer treatment. We previously identified epiregulin (EREG), an EGF-like ligand, as a gene upregulated in several mouse lung cancer models. Therefore, our overall hypothesis for these studies was that EREG has a critical role in early stage lung tumor development. We used a primary two-stage initiation/promotion model with 3-methylcholanthrene (initiator) followed by multiple weekly exposures to butylated hydroxytoluene (BHT; promoter) in mice lacking Ereg (Ereg-/-) and wildtype controls (Ereg+/+) and examined multiple time points and endpoints (bronchoalveolar lavage analysis, tumor analysis, mRNA expression, ELISA) during tumor promotion. We also investigated the role of EREG in both non-tumorigenic, ADC, and SCC cell lines. At the early time points (4 and 12 wk), we observed significantly reduced amounts of inflammation (macrophages, PMNs) in the Ereg-/- mice compared to controls (Ereg+/+). At 20 weeks, tumor multiplicity was also significantly decreased in the Ereg-/- mice vs controls (Ereg+/+). EREG was significantly up-regulated in both ADC (A549) and SCC (SW900 SK-MES1) cell lines, but not non-tumorigenic lines (BEAS2B, HBEC, HBE1). However, recombinant EREG elicited both significantly increased wound healing and proliferation in BEAS2B cells. These results indicate that EREG has potential utility as an early cancer prognostic biomarker. The impact of EREG on tumor development may lead to future therapeutic interventions using small peptide inhibitors or vaccines against EREG.
Funded by the American Cancer Society.