Research Papers:

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

Mengyao Sun _, Yang Bai, Song Zhao, Xiyu Liu, Yongsheng Gao, Lei Wang, Bin Liu, Dashi Ma and Chunye Ma

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Oncotarget. 2018; 9:13462-13473. https://doi.org/10.18632/oncotarget.24008

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Mengyao Sun1, Yang Bai1, Song Zhao2, Xiyu Liu3, Yongsheng Gao1, Lei Wang1, Bin Liu1, Dashi Ma1 and Chunye Ma1

1The Cardiac Surgery Department, The First Hospital of Jilin University, Changchun 130021, China

2The Spine Surgery Department, The First Hospital of Jilin University, Changchun 130021, China

3The Thoracic Surgery Department, Affiliated Hospital of Guilin Medical University, Guilin 541001, China

Correspondence to:

Chunye Ma, email: [email protected]

Dashi Ma, email: [email protected]

Keywords: gram-negative bacteria; NSCLC; TLR4; IL-33

Abbreviations: NSCLC: non-small-cell lung cancer; TLR4: Toll-like receptor 4; MyD88: myeloid differentiation primary-response protein 88; IL-33: interleukin-33

Received: October 10, 2017     Accepted: November 13, 2017     Published: January 04, 2018


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.

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