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000181827 041__ $$aEnglish
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000181827 1001_ $$00000-0001-9971-9733$$aBaranašić, Jurica$$b0
000181827 245__ $$aTLR5 Variants Are Associated with the Risk for COPD and NSCLC Development, Better Overall Survival of the NSCLC Patients and Increased Chemosensitivity in the H1299 Cell Line.
000181827 260__ $$aBasel$$bMDPI$$c2022
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000181827 520__ $$aChronic obstructive pulmonary disease (COPD) is considered as the strongest independent risk factor for lung cancer (LC) development, suggesting an overlapping genetic background in both diseases. A common feature of both diseases is aberrant immunity in respiratory epithelia that is mainly regulated by Toll-like receptors (TLRs), key regulators of innate immunity. The function of the flagellin-sensing TLR5 in airway epithelia and pathophysiology of COPD and LC has remained elusive. We performed case-control genetic association and functional studies on the importance of TLR5 in COPD and LC development, comparing Caucasian COPD/LC patients (n = 974) and healthy donors (n = 1283). Association analysis of three single nucleotide polymorphisms (SNPs) (rs725084, rs2072493_N592S, and rs5744174_F616L) indicated the minor allele of rs2072493_N592S to be associated with increased risk for COPD (OR = 4.41, p < 0.0001) and NSCLC (OR = 5.17, p < 0.0001) development and non-small cell LC risk in the presence of COPD (OR = 1.75, p = 0.0031). The presence of minor alleles (rs5744174 and rs725084) in a co-dominant model was associated with overall survival in squamous cell LC patients. Functional analysis indicated that overexpression of the rs2072493_N592S allele affected the activation of NF-κB and AP-1, which could be attributed to impaired phosphorylation of p38 and ERK. Overexpression of TLR5N592S was associated with increased chemosensitivity in the H1299 cell line. Finally, genome-wide transcriptomic analysis on WI-38 and H1299 cells overexpressing TLR5WT or TLR5N592S, respectively, indicated the existence of different transcription profiles affecting several cellular pathways potentially associated with a dysregulated immune response. Our results suggest that TLR5 could be recognized as a potential biomarker for COPD and LC development with functional relevance.
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000181827 650_7 $$2Other$$aCOPD
000181827 650_7 $$2Other$$aNSCLC
000181827 650_7 $$2Other$$aSNP
000181827 650_7 $$2Other$$aTLR5
000181827 650_7 $$2Other$$achemoresistance
000181827 650_7 $$2Other$$asurvival
000181827 7001_ $$aŠutić, Maja$$b1
000181827 7001_ $$aCatalano, Calogerina$$b2
000181827 7001_ $$aDrpa, Gordana$$b3
000181827 7001_ $$aHuhn, Stefanie$$b4
000181827 7001_ $$00000-0003-0385-0900$$aMajhen, Dragomira$$b5
000181827 7001_ $$00000-0002-5518-5650$$aNestić, Davor$$b6
000181827 7001_ $$aKurtović, Matea$$b7
000181827 7001_ $$aRumora, Lada$$b8
000181827 7001_ $$aBosnar, Martina$$b9
000181827 7001_ $$00000-0002-1522-3325$$aVukić Dugac, Andrea$$b10
000181827 7001_ $$00000-0001-5210-9196$$aSokolović, Irena$$b11
000181827 7001_ $$00000-0003-2513-9079$$aPopovic-Grle, Sanja$$b12
000181827 7001_ $$00000-0001-5102-3606$$aOršolić, Nada$$b13
000181827 7001_ $$aŠkrinjarić-Cincar, Sanda$$b14
000181827 7001_ $$00000-0002-4815-7512$$aJakopović, Marko$$b15
000181827 7001_ $$aSamaržija, Miroslav$$b16
000181827 7001_ $$aWeber, Alexander N R$$b17
000181827 7001_ $$0P:(DE-He78)f26164c08f2f14abcf31e52e13ee3696$$aFörsti, Asta$$b18$$eLast author$$udkfz
000181827 7001_ $$aKnežević, Jelena$$b19
000181827 773__ $$0PERI:(DE-600)2720867-9$$a10.3390/biomedicines10092240$$gVol. 10, no. 9, p. 2240 -$$n9$$p2240$$tBiomedicines$$v10$$x2227-9059$$y2022
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