Requirement for MUC5AC in KRAS-dependent lung carcinogenesis.

Autor: Bauer AK; Department of Environmental and Occupational Health, Colorado School of Public Health, University of Colorado, Aurora, Colorado, USA., Umer M; Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Richardson VL; Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, Colorado, USA., Cumpian AM; Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Harder AQ; Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, Colorado, USA., Khosravi N; Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Azzegagh Z; Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Hara NM; Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, Colorado, USA., Ehre C; Marsico Lung Institute/CF Center, Department of Pediatrics, University of North Carolina - Chapel Hill, Chapel Hill, North Carolina, USA., Mohebnasab M; Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Caetano MS; Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Merrick DT; Department of Pathology, University of Colorado, Aurora, Colorado, USA., van Bokhoven A; Department of Pathology, University of Colorado, Aurora, Colorado, USA., Wistuba II; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Kadara H; Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.; Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Dickey BF; Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Velmurugan K; Department of Environmental and Occupational Health, Colorado School of Public Health, University of Colorado, Aurora, Colorado, USA., Mann PR; Department of Pathology, University of Colorado, Aurora, Colorado, USA., Lu X; Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado, Aurora, Colorado, USA., Barón AE; Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado, Aurora, Colorado, USA., Evans CM; Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, Colorado, USA., Moghaddam SJ; Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2018 Aug 09; Vol. 3 (15). Date of Electronic Publication: 2018 Aug 09 (Print Publication: 2018).
DOI: 10.1172/jci.insight.120941
Abstrakt: With more than 150,000 deaths per year in the US alone, lung cancer has the highest number of deaths for any cancer. These poor outcomes reflect a lack of treatment for the most common form of lung cancer, non-small cell lung carcinoma (NSCLC). Lung adenocarcinoma (ADC) is the most prevalent subtype of NSCLC, with the main oncogenic drivers being KRAS and epidermal growth factor receptor (EGFR). Whereas EGFR blockade has led to some success in lung ADC, effective KRAS inhibition is lacking. KRAS-mutant ADCs are characterized by high levels of gel-forming mucin expression, with the highest mucin levels corresponding to worse prognoses. Despite these well-recognized associations, little is known about roles for individual gel-forming mucins in ADC development causatively. We hypothesized that MUC5AC/Muc5ac, a mucin gene known to be commonly expressed in NSCLC, is crucial in KRAS/Kras-driven lung ADC. We found that MUC5AC was a significant determinant of poor prognosis, especially in patients with KRAS-mutant tumors. In addition, by using mice with lung ADC induced chemically with urethane or transgenically by mutant-Kras expression, we observed significantly reduced tumor development in animals lacking Muc5ac compared with controls. Collectively, these results provide strong support for MUC5AC as a potential therapeutic target for lung ADC, a disease with few effective treatments.
Databáze: MEDLINE