%0 Journal Article
%A Baranašić, Jurica
%A Šutić, Maja
%A Catalano, Calogerina
%A Drpa, Gordana
%A Huhn, Stefanie
%A Majhen, Dragomira
%A Nestić, Davor
%A Kurtović, Matea
%A Rumora, Lada
%A Bosnar, Martina
%A Vukić Dugac, Andrea
%A Sokolović, Irena
%A Popovic-Grle, Sanja
%A Oršolić, Nada
%A Škrinjarić-Cincar, Sanda
%A Jakopović, Marko
%A Samaržija, Miroslav
%A Weber, Alexander N R
%A Försti, Asta
%A Knežević, Jelena
%T TLR5 Variants Are Associated with the Risk for COPD and NSCLC Development, Better Overall Survival of the NSCLC Patients and Increased Chemosensitivity in the H1299 Cell Line.
%J Biomedicines
%V 10
%N 9
%@ 2227-9059
%C Basel
%I MDPI
%M DKFZ-2022-02242
%P 2240
%D 2022
%Z #LA:B062#
%X Chronic obstructive pulmonary disease (COPD) is considered as the strongest independent risk factor for lung cancer (LC) development, suggesting an overlapping genetic background in both diseases. A common feature of both diseases is aberrant immunity in respiratory epithelia that is mainly regulated by Toll-like receptors (TLRs), key regulators of innate immunity. The function of the flagellin-sensing TLR5 in airway epithelia and pathophysiology of COPD and LC has remained elusive. We performed case-control genetic association and functional studies on the importance of TLR5 in COPD and LC development, comparing Caucasian COPD/LC patients (n = 974) and healthy donors (n = 1283). Association analysis of three single nucleotide polymorphisms (SNPs) (rs725084, rs2072493_N592S, and rs5744174_F616L) indicated the minor allele of rs2072493_N592S to be associated with increased risk for COPD (OR = 4.41, p < 0.0001) and NSCLC (OR = 5.17, p < 0.0001) development and non-small cell LC risk in the presence of COPD (OR = 1.75, p = 0.0031). The presence of minor alleles (rs5744174 and rs725084) in a co-dominant model was associated with overall survival in squamous cell LC patients. Functional analysis indicated that overexpression of the rs2072493_N592S allele affected the activation of NF-κB and AP-1, which could be attributed to impaired phosphorylation of p38 and ERK. Overexpression of TLR5N592S was associated with increased chemosensitivity in the H1299 cell line. Finally, genome-wide transcriptomic analysis on WI-38 and H1299 cells overexpressing TLR5WT or TLR5N592S, respectively, indicated the existence of different transcription profiles affecting several cellular pathways potentially associated with a dysregulated immune response. Our results suggest that TLR5 could be recognized as a potential biomarker for COPD and LC development with functional relevance.
%K COPD (Other)
%K NSCLC (Other)
%K SNP (Other)
%K TLR5 (Other)
%K chemoresistance (Other)
%K survival (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:36140341
%R 10.3390/biomedicines10092240
%U https://inrepo02.dkfz.de/record/181827