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Requirement for MUC5AC in KRAS-dependent lung carcinogenesis.

Bauer, Alison K and Umer, Misha and Richardson, Vanessa L and Cumpian, Amber M and Harder, Anna Q and Khosravi, Nasim and Azzegagh, Zoulikha and Hara, Naoko M and Ehre, Camille and Mohebnasab, Maedeh and Caetano, Mauricio S and Merrick, Daniel T and van Bokhoven, Adrie and Wistuba, Ignacio I and Kadara, Humam and Dickey, Burton F and Velmurugan, Kalpana and Mann, Patrick R and Lu, Xian and Barón, Anna E and Evans, Christopher M and Moghaddam, Seyed Javad (2018) Requirement for MUC5AC in KRAS-dependent lung carcinogenesis. JCI Insight, 3 (15).

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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.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Bauer, Alison K
Umer, Misha
Richardson, Vanessa L
Cumpian, Amber M
Harder, Anna Q
Khosravi, Nasim
Azzegagh, Zoulikha
Hara, Naoko M
Ehre, Camille
Mohebnasab, MaedehMAM1236@pitt.eduMAM12360000-0001-6623-9514
Caetano, Mauricio S
Merrick, Daniel T
van Bokhoven, Adrie
Wistuba, Ignacio I
Kadara, Humam
Dickey, Burton F
Velmurugan, Kalpana
Mann, Patrick R
Lu, Xian
Barón, Anna E
Evans, Christopher M
Moghaddam, Seyed Javad
Date: 29 June 2018
Date Type: Acceptance
Journal or Publication Title: JCI Insight
Volume: 3
Number: 15
DOI or Unique Handle: 10.1172/jci.insight.120941
Schools and Programs: School of Medicine > Pathology
Refereed: Yes
Uncontrolled Keywords: Lung cancer, Oncology, Pulmonology, Adenocarcinoma of Lung, Animals, Biomarkers, Tumor, Carcinogenesis, Carcinoma, Non-Small-Cell Lung, ErbB Receptors, Female, Humans, Lung, Lung Neoplasms, Male, Mice, Mice, Transgenic, Mucin 5AC, Mutation, Neoplasms, Experimental, Prognosis, Proto-Oncogene Proteins p21(ras), Survival Analysis
Funders: NCI NIH HHS (P50 CA058187), NHLBI NIH HHS (R01 HL080396), NCI NIH HHS (P30 CA046934), NHLBI NIH HHS (R01 HL129795), NHLBI NIH HHS (R01 HL130938)
Date Deposited: 29 Aug 2022 17:08
Last Modified: 03 Sep 2022 06:55


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