title: Epiregulin is required for lung tumor promotion in a murine two-stage carcinogenesis model.
abstract: Adenocarcinoma accounts for ∼40% of lung cancer, equating to ∼88 500 new patients in 2015, most of who will succumb to this disease, thus, the public health burden is evident. 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 biomarker in several mouse lung cancer models. In the present investigation we used a primary two-stage initiation/promotion model to test our hypothesis that Ereg deficiency would reduce lung tumor promotion in mice. We used 3-methylcholanthrene (initiator) or oil vehicle followed by multiple weekly exposures to butylated hydroxytoluene (BHT; promoter) in mice lacking Ereg (Ereg-/-) and wildtype controls (BALB/ByJ; Ereg+/+) and examined multiple time points and endpoints (bronchoalveolar lavage analysis, tumor analysis, mRNA expression, ELISA, wound assay) during tumor promotion. 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 wk, tumor multiplicity was also significantly decreased in the Ereg-/-mice versus controls (Ereg+/+). IL10 expression, an anti-inflammatory mediator, and downstream signaling events (Stat3) were significantly increased in the Ereg-/-mice in response to BHT, supporting both reduced inflammation and tumorigenesis. Lastly, wound healing was significantly increased with recombinant Ereg in both human and mouse lung epithelial cell lines. These results indicate that Ereg has proliferative potential and may be utilized as an early cancer biomarker as well as a novel potential therapeutic target. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Environmental and Occupational Health, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado.
authors.forename: Alison K
authors.initials: AK
authors.lastname: Bauer
authors.affiliation: Department of Environmental and Occupational Health, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado.
authors.forename: Kalpana
authors.initials: K
authors.lastname: Velmurugan
authors.affiliation: Department of Environmental and Occupational Health, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado.
authors.forename: Ka-Na
authors.initials: KN
authors.lastname: Xiong
authors.affiliation: Department of Environmental and Occupational Health, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado.
authors.forename: Carla-Maria
authors.initials: CM
authors.lastname: Alexander
authors.affiliation: Department of Environmental and Occupational Health, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado.
authors.forename: Julie
authors.initials: J
authors.lastname: Xiong
authors.affiliation: Department of Environmental and Occupational Health, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado.
authors.forename: Rana
authors.initials: R
authors.lastname: Brooks
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D002084:Butylated Hydroxytoluene; D063646:Carcinogenesis / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D066260:Epiregulin / Q000235:genetics*; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D008168:Lung / Q000473:pathology*; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D066260:Epiregulin; D002084:Butylated Hydroxytoluene
keywords: BHT; epiregulin; inflammation; lung; tumor promotion