TY  - JOUR
AU  - Baranašić, Jurica
AU  - Šutić, Maja
AU  - Catalano, Calogerina
AU  - Drpa, Gordana
AU  - Huhn, Stefanie
AU  - Majhen, Dragomira
AU  - Nestić, Davor
AU  - Kurtović, Matea
AU  - Rumora, Lada
AU  - Bosnar, Martina
AU  - Vukić Dugac, Andrea
AU  - Sokolović, Irena
AU  - Popovic-Grle, Sanja
AU  - Oršolić, Nada
AU  - Škrinjarić-Cincar, Sanda
AU  - Jakopović, Marko
AU  - Samaržija, Miroslav
AU  - Weber, Alexander N R
AU  - Försti, Asta
AU  - Knežević, Jelena
TI  - 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.
JO  - Biomedicines
VL  - 10
IS  - 9
SN  - 2227-9059
CY  - Basel
PB  - MDPI
M1  - DKFZ-2022-02242
SP  - 2240
PY  - 2022
N1  - #LA:B062#
AB  - 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.
KW  - COPD (Other)
KW  - NSCLC (Other)
KW  - SNP (Other)
KW  - TLR5 (Other)
KW  - chemoresistance (Other)
KW  - survival (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:36140341
DO  - DOI:10.3390/biomedicines10092240
UR  - https://inrepo02.dkfz.de/record/181827
ER  -