Requirement for MUC5AC in KRAS-dependent lung carcinogenesis
Alison K. Bauer, Misha Umer, Vanessa L. Richardson, Amber M. Cumpian, Anna Q. Harder, Nasim Khosravi, Zoulikha Azzegagh, Naoko M. Hara, Camille Ehre, Maedeh Mohebnasab, Mauricio S. Caetano, Daniel T. Merrick, Adrie van Bokhoven, Ignacio I. Wistuba, Humam Kadara, Burton F. Dickey, Kalpana Velmurugan, Patrick R. Mann, Xian Lu, Anna E. Barón, Christopher M. Evans, Seyed Javad Moghaddam
Alison K. Bauer, Misha Umer, Vanessa L. Richardson, Amber M. Cumpian, Anna Q. Harder, Nasim Khosravi, Zoulikha Azzegagh, Naoko M. Hara, Camille Ehre, Maedeh Mohebnasab, Mauricio S. Caetano, Daniel T. Merrick, Adrie van Bokhoven, Ignacio I. Wistuba, Humam Kadara, Burton F. Dickey, Kalpana Velmurugan, Patrick R. Mann, Xian Lu, Anna E. Barón, Christopher M. Evans, Seyed Javad Moghaddam
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Research Article Oncology Pulmonology

Requirement for MUC5AC in KRAS-dependent lung carcinogenesis

Abstract

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.

Authors

Alison K. Bauer, Misha Umer, Vanessa L. Richardson, Amber M. Cumpian, Anna Q. Harder, Nasim Khosravi, Zoulikha Azzegagh, Naoko M. Hara, Camille Ehre, Maedeh Mohebnasab, Mauricio S. Caetano, Daniel T. Merrick, Adrie van Bokhoven, Ignacio I. Wistuba, Humam Kadara, Burton F. Dickey, Kalpana Velmurugan, Patrick R. Mann, Xian Lu, Anna E. Barón, Christopher M. Evans, Seyed Javad Moghaddam

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Figure 1

MUC5AC production is associated with human lung ADC and poor survival.

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MUC5AC production is associated with human lung ADC and poor survival. (...
(A–C) MUC5AC protein levels were analyzed immunohistochemically using human tissue arrays. Representative images of MUC5AC immunostaining in adenocarcinoma (ADC) (A) and squamous cell carcinoma (SCC) (B) are shown. Scale bars: 200 μm (low magnification) and 10 μm (high magnification). (C) MUC5AC H-scores for ADC (n = 53) and adenosquamous (n = 3) (combined and included with ADC, red circles) were compared with SCC (n = 21, gray circles). MUC5AC levels were significantly higher in ADC tissues. Data are individual values with lines depicting medians ± 95% CIs. Significance was determined by the Wilcoxon rank sum test (61). P < 0.05. (D–F) Effects of MUC5AC expression on survival in ADC and SCC were tested using KM Plotter (http://kmplot.com/analysis/). MUC5AC expression was stratified to define high- (red) and low-expression (black) groups by median transcript levels. Kaplan-Meier survival plot and hazard ratio calculations were compared by multivariate log-rank analyses with sex and stage as covariates; P < 0.05. While sex was not significant, stage was strongly significant for ADC (log-rank P < 1 × 10–14). Significant effects of high MUC5AC gene expression were observed for all human lung ADC (D, n = 534, log-rank P < 0.0001) and for stage I ADC (E, n = 370, log-rank P = 0.001) samples. No differences were observed in SCC (F, n = 315, log-rank P = 0.62). For all groups in D–F, calculated hazard ratios were 2.0 (1.5–2.7) for all ADC, 1.9 (1.3–2.8) for stage I ADC, and 1.1 (0.8–1.5) for SCC.