TY - JOUR
T1 - Augmented Lipocalin-2 Is Associated with Chronic Obstructive Pulmonary Disease and Counteracts Lung Adenocarcinoma Development
AU - Treekitkarnmongkol, Warapen
AU - Hassane, Maya
AU - Sinjab, Ansam
AU - Chang, Kyle
AU - Hara, Kieko
AU - Rahal, Zahraa
AU - Zhang, Jiexin
AU - Lu, Wei
AU - Sivakumar, Smruthy
AU - McDowell, Tina L.
AU - Kantrowitz, Jacob
AU - Zhou, Jianling
AU - Lang, Wenhua
AU - Xu, Li
AU - Ochieng, Joshua K.
AU - Nunomura-Nakamura, Sayuri
AU - Deng, Shanshan
AU - Behrens, Carmen
AU - Raso, Maria Gabriela
AU - Fukuoka, Junya
AU - Reuben, Alexandre
AU - Ostrin, Edwin J.
AU - Parra, Edwin
AU - Solis, Luisa M.
AU - Spira, Avrum E.
AU - McAllister, Florencia
AU - Cascone, Tina
AU - Wistuba, Ignacio I.
AU - Moghaddam, Seyed Javad
AU - Scheet, Paul A.
AU - Fujimoto, Junya
AU - Kadara, Humam
N1 - Funding Information:
Supported in part by National Cancer Institute grant R01CA205608 (H.K.), American Lung Association Lung Cancer Discovery Award (H.K.), University Cancer Foundation Institutional Research Grant (H.K.), and a Medical Practice Plan grant from American University of Beirut (H.K.).
Publisher Copyright:
Copyright © 2021 by the American Thoracic Society
PY - 2021/1/1
Y1 - 2021/1/1
N2 - Rationale: Early pathogenesis of lung adenocarcinoma (LUAD) remains largely unknown. We found that, relative to wild-type littermates, the innate immunomodulator Lcn2 (lipocalin-2) was increased in normal airways from mice with knockout of the airway lineage gene Gprc5a (Gprc5a2/2) and that are prone to developing inflammation and LUAD. Yet, the role of LCN2 in lung inflammation and LUAD is poorly understood. Objectives: Delineate the role of Lcn2 induction in LUAD pathogenesis. Methods: Normal airway brushings, uninvolved lung tissues, and tumors from Gprc5a2/2 mice before and after tobacco carcinogen exposure were analyzed by RNA sequencing. LCN2 mRNA was analyzed in public and in-house data sets of LUAD, lung squamous cancer (LUSC), chronic obstructive pulmonary disease (COPD), and LUAD/LUSC with COPD. LCN2 protein was immunohistochemically analyzed in a tissue microarray of 510 tumors. Temporal lung tumor development, gene expression programs, and host immune responses were compared between Gprc5a2/2 and Gprc5a2/2/Lcn22/2 littermates. Measurements and Main Results: Lcn2 was progressively elevated during LUAD development and positively correlated with proinflammatory cytokines and inflammation gene sets. LCN2 was distinctively elevated in human LUADs, but not in LUSCs, relative to normal lungs and was associated with COPD among smokers and patients with LUAD. Relative to Gprc5a2/2 mice, Gprc5a2/2/Lcn22/2 littermates exhibited significantly increased lung tumor development concomitant with reduced T-cell abundance (CD41) and richness, attenuated antitumor immune gene programs, and increased immune cell expression of protumor inflammatory cytokines. Conclusions: Augmented LCN2 expression is a molecular feature of COPD-associated LUAD and counteracts LUAD development in vivo by maintaining antitumor immunity.
AB - Rationale: Early pathogenesis of lung adenocarcinoma (LUAD) remains largely unknown. We found that, relative to wild-type littermates, the innate immunomodulator Lcn2 (lipocalin-2) was increased in normal airways from mice with knockout of the airway lineage gene Gprc5a (Gprc5a2/2) and that are prone to developing inflammation and LUAD. Yet, the role of LCN2 in lung inflammation and LUAD is poorly understood. Objectives: Delineate the role of Lcn2 induction in LUAD pathogenesis. Methods: Normal airway brushings, uninvolved lung tissues, and tumors from Gprc5a2/2 mice before and after tobacco carcinogen exposure were analyzed by RNA sequencing. LCN2 mRNA was analyzed in public and in-house data sets of LUAD, lung squamous cancer (LUSC), chronic obstructive pulmonary disease (COPD), and LUAD/LUSC with COPD. LCN2 protein was immunohistochemically analyzed in a tissue microarray of 510 tumors. Temporal lung tumor development, gene expression programs, and host immune responses were compared between Gprc5a2/2 and Gprc5a2/2/Lcn22/2 littermates. Measurements and Main Results: Lcn2 was progressively elevated during LUAD development and positively correlated with proinflammatory cytokines and inflammation gene sets. LCN2 was distinctively elevated in human LUADs, but not in LUSCs, relative to normal lungs and was associated with COPD among smokers and patients with LUAD. Relative to Gprc5a2/2 mice, Gprc5a2/2/Lcn22/2 littermates exhibited significantly increased lung tumor development concomitant with reduced T-cell abundance (CD41) and richness, attenuated antitumor immune gene programs, and increased immune cell expression of protumor inflammatory cytokines. Conclusions: Augmented LCN2 expression is a molecular feature of COPD-associated LUAD and counteracts LUAD development in vivo by maintaining antitumor immunity.
KW - Chronic obstructive pulmonary disease
KW - Immunity
KW - Lipocalin-2
KW - Lung neoplasms
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U2 - 10.1164/rccm.202004-1079OC
DO - 10.1164/rccm.202004-1079OC
M3 - Article
C2 - 32730093
AN - SCOPUS:85098652053
SN - 1073-449X
VL - 203
SP - 90
EP - 101
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 1
ER -