The SARS-CoV-2 spike protein induces lung cancer migration and invasion in a TLR2-dependent manner

Abstract

Abbreviations SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 TLR toll-like receptor NSCLC non-small cell lung cancer ACE2 angiotensin-converting enzyme 2 TMPRSS2 transmembrane protease serine subtype 2 GSEA gene set enrichment analysis Pam3CSK4 tripalmitoyl-S-glycero-Cys-(Lys) 4 FSL-1 fibroblast stimulating lipopeptide 1 NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells IKK inhibitor of nuclear factor-κB kinase ERK extracellular signal-regulated kinase CRISPR-Cas9 clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 Dear editor, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to severe outcomes in patients with cancer [ 1]. Abbreviations: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TLR, toll-like receptor; NSCLC, non-small cell lung cancer; ∆Mag; magnitude difference; ACE2, angiotensin-converting enzyme 2; TMPRSS2, transmembrane protease serine subtype 2; LTTs, lung tumor tissues; mLNTs, matched lung normal tissues; GSEA, gene set enrichment analysis; IL-1R, interleukin-1 receptor; TNF, tumor necrosis factor; Pam3CSK4, tripalmitoyl-S-glycero-Cys-(Lys) 4; FSL-1, fibroblast stimulating lipopeptide 1; TLR2-KO, TLR2-knockout; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; ELISA, enzyme-linked immunosorbent assay; IKK, inhibitor of nuclear factor-κB kinase; ERK, extracellular signal-regulated kinase; CRISPR-Cas9, clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9; IL-6, interleukin 6. SARS-CoV-2 virus can infect human cells and induce inflammatory cytokines and chemokines, including IL-6, IL-1β, TNF-α, C-X-C motif chemokine ligand 1 (CXCL1), CXCL2, and C-C motif chemokine ligand 2 (CCL2), via TLR2-dependent activation of the NF-κB pathway [ 3–6]. [...]we further assessed whether expression levels of ACE2, TMPRSS2, TLR1, TLR2, and TLR6 were associated with gene sets related to inflammatory cytokines and chemokines. Upon treatment with the SARS-CoV-2 S protein, Pam3CSK4 (an agonist of TLR1/2), or FSL-1 (an agonist of TLR2/6), migration and invasion abilities of A549 and H1299 lung cancer cells were significantly enhanced compared to those upon treatment with vehicle control (Figure 1G-H, Supplementary Figure S6). [...]colony-forming and cell proliferation assay revealed significant increases in response to the SARS-CoV-2 S protein, Pam3CSK4, or FSL-1 (Supplementary Figure S7).