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  • br Conclusions IRF levels in WBCs can be

    2019-11-11


    Conclusions: IRF5 levels in WBCs can be significantly upregulated in early stage NSCLC and were shown to have diagnostic value as an early warning biomarker of NSCLC development.
    1. Introduction
    Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer-related deaths worldwide [1]. Non-small cell lung cancer (NSCLC) accounts for 85%–90% of lung cancer cases and in-cludes two subtypes: lung squamous cell carcinoma and lung adeno-carcinoma [2]. The survival of patients with lung cancer is strongly related to the cancer stage as evidenced by a steep decrease in the 5-year overall survival rate from 82% in stage IA to 6% in stage IV [3]. However, in routine clinical practise, many patients with early stage
    lung cancer are not diagnosed in due time because they are often asymptomatic [4]. As a result, at the time of diagnosis, approximately 70% of NSCLC patients already have locally advanced or metastatic tumours [5]. Reliable early warning indicators of NSCLC development should improve the survival of lung cancer patients; however, these indicators are not currently available and need to be identified.
    Cancer Liproxstatin-1 evolve from normal cells altered by gene mutations. Normally, the body’s surveillance system, the immune system, responds to the altered cells by initiating inflammation, which is a critical component of the innate immune response to harmful stimuli [6]. In
    Abbreviations: IRF5, interferon regulatory factor 5; NSCLC, non-small cell lung cancer; AD, adenocarcinoma; SQ, squamous cell carcinoma; CT, cancer tissues; PCT, para-carcinoma tissues; ES, early stage; PS, progressive stage; HC, healthy controls; AUC, area under the receiver-operating characteristics curve; CI, confidence interval; OR, odds ratio; WBCs, white blood cells; NE, neutrophil; MO, monocyte; LY, lymphocyte; qRT-PCR, quantitative reverse transcription-polymerase chain reaction
    Corresponding author at: Department of Respiratory Medicine, The First Affiliated Hospital of Jilin University, Jilin University, No. 71, Xinmin Street, Changchun, Jilin, 130021, PR Liproxstatin-1 China.
    1863, Rudolf Virchow provided the first indication of a possible link between inflammation and cancer when he observed the presence of leucocytes in neoplastic tissues [7]. Research in recent decades provides abundant evidence of the role played by inflammation in tumorigenesis [8]. Inflammation supplies the tumour microenvironment with bioac-tive molecules activating epithelial-mesenchymal transition (EMT), growth factors and chemokines that support cell proliferation and in-hibit death, and pro-angiogenic factors, extracellular matrix-modifying enzymes that facilitate tumour angiogenesis, invasion, and metastasis, thus promoting cancer progression [9–12]. The link between in-flammation and cancer is confirmed by the activation of nuclear factor-κB (NF-κB), a key transcription factor. The activated NF-κB in in-flammatory immune cells can lead to the production of inflammatory mediators that support the growth and survival of carcinoma cells. If NF-κB is activated in malignant cells, it can result in the elevated ex-pression of cell-cycle genes, apoptosis inhibitors, and proteases that promote the invasive phenotype [13]. Furthermore, tumour cell-de-rived inflammatory mediators can activate pattern recognition re-ceptors (PRRs), which are critical for triggering innate immune re-sponses [10]. A PRR expressed on innate immune cells can also recognise its ligand expressed on tumour cells to trigger anti-tumour responses [14].
    In innate immune cells, PRR activation upregulates the expression of many inflammatory genes, including those coding for NF-κB and interferon regulatory factors (IRFs). IRF5 is an IRF family member with diverse immunomodulatory activities [15]. IRF5 is regulated through the activation of Toll-like receptors (TLRs), a type of PRR that results in the formation of the MyD88-IRF5-TRAF6 complex [16] and the release of IRF5 from its C-terminal self-inhibition through phosphorylation [17]. The phosphorylated IRF5 is translocated from the cytoplasm into the nucleus, where it binds the IFN-stimulated response element (ISRE) and promotes transcription of the target genes [18]. Through such ac-tivity, IRF5 regulates type I IFNs and directly induces the expression of pro-inflammatory cytokines/chemokines such as IL-6, TNF-α, IL-12, macrophage inflammatory protein 1-alpha (MIP-1-α), and IFNγ-in-duced protein (IP)-10, while repressing the transcription of anti-in-flammatory cytokines such as IL-10 [16,19–21]. IRF5, which is ex-pressed in many immune cells including monocytes, macrophages, dendritic cells, B cells, and neutrophils [22,23], was shown to play a pivotal role in the inflammatory polarisation of monocytes/macro-phages [21,24], regulation of B cell activation, proliferation, plasma-blast differentiation [25,26], and in the recruitment of neutrophils to sites of inflammation [27].