Gram-negative bacteria facilitate tumor progression through TLR4/IL-33 pathway in patients with non-small-cell lung cancer

Abstract

Non-small-cell lung cancer (NSCLC) accounts for the most cases in clinical lung cancer patients. Patients with NSCLC are often diagnosed in advanced stage and frequently infected with gram-negative bacteria. Pulmonary infection with gram-negative bacteria is the most frequent postoperative complication in NSCLC patients. While accumulating evidence indicate an involvement of gram-negative bacteria in NSCLC progression, the underlying mechanisms remain largely unknown. Herein, we explored the effect of gram-negative bacteria on tumor progression using tumor cells from NSCLC patients. We observed that infection with gram-negative bacteria predicted advanced stages and decreased time interval to recurrence of NSCLC patients. Incubation of NSCLC cells with gram-negative bacteria promoted their growth and metastasis. Mechanistically, gram-negative bacteria activated Toll-like receptor 4 (TLR4) signaling in NSCLC cells, leading to increased mRNA and protein expression of interleukin 33 (IL-33) through MyD88-dependent pathway. Knockdown of IL-33 abrogated the contribution of gram-negative bacteria to NSCLC progression by regulating cancer metabolic activities and stem cell properties. In NSCLC patients, higher TLR4 expression was associated with increased IL-33 expression, Ki-67 proliferation index and CD133 expression in those with gram-negative bacterial infection. These findings shed new light on the molecular mechanisms underlie gram-negative bacteria mediated tumor progression and provide clues for innovative therapeutic explorations for NSCLC patients.