IL-1β-Mediated Repression of microRNA-101 Is Crucial for Inflammation-Promoted Lung Tumorigenesis

Wang, Lin; Zhang, Ling-Fei; Wu, Jing; Xu, Shujun; Xu, Yangyang; Li, Dangsheng; Lou, Jiatao; Lin, Li

doi:10.1158/0008-5472.can-14-0960

Cited by 103 publications

(87 citation statements)

References 48 publications

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“…Although the mechanisms by which IL-1β impacts lung tumor biology are not fully understood, our findings suggest that IL-1β exerts its pro-tumorigenic effects by promoting proliferation of lung epithelial cells. Our observations are consistent with a prior report that IL-1β increases proliferation of human NSCLC cells (Wang et al, 2014). …”

Section: Discussionsupporting

confidence: 94%

Neutrophil-Derived IL-1β Impairs the Efficacy of NF-κB Inhibitors against Lung Cancer

et al. 2016

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SUMMARY While epithelial NF-κB signaling is important for lung carcinogenesis, NF-κB inhibitors are ineffective for cancer treatment. To explain this paradox, we studied mice with genetic deletion of IKKβ in myeloid cells and found enhanced tumorigenesis in KrasG12D and urethane models of lung cancer. Myeloid-specific inhibition of NF-κB augmented pro-IL-1β processing by cathepsin G in neutrophils, leading to increased IL-1β and enhanced epithelial cell proliferation. Combined treatment with bortezomib, a proteasome inhibitor that blocks NF-κB activation, and IL-1 receptor antagonist reduced tumor formation and growth in vivo. In lung cancer patients, plasma IL-1β levels correlated with poor prognosis and IL-1β increased following bortezomib treatment. Together, our studies elucidate an important role for neutrophils and IL-1β in lung carcinogenesis and resistance to NF-κB inhibitors.

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Section: Discussionsupporting

confidence: 94%

Neutrophil-Derived IL-1β Impairs the Efficacy of NF-κB Inhibitors against Lung Cancer

et al. 2016

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“…Inflammation is a contributor to NSCLC progression [10–12], and C5a can cause tumor cell proliferation [8, 9, 28, 29]. However, how C5a affects tumor cell proliferation in NSCLC still remains obscure.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, some pro-inflammatory factors such as IL-1 and IL-6 can upregulate C5aR expression during the process of other diseases [32, 33]. These factors, which also exist in NSCLC microenvironment [10], might elevate C5aR expression in NSCLC cells, and finally promoting NSCLC development and progression together with C5a.…”

Section: Discussionmentioning

confidence: 99%

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C5a induces A549 cell proliferation of non-small cell lung cancer via GDF15 gene activation mediated by GCN5-dependent KLF5 acetylation

Zhao

Qiu

et al. 2018

Oncogene

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Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and multiple evidence has confirmed that C5a production is elevated in NSCLC microenvironment. Although NSCLC cell proliferation induced by C5a has been reported, the involved mechanism has not been elucidated. In this study, we examined the proliferation-related genes (i.e., KLF5, GCN5, and GDF15) and C5a receptor (C5aR) expression in tumor tissues as well as C5a concentration in plasma of NSCLC patients, and then determined the roles of KLF5, GCN5, and GDF15 in C5a-triggered NSCLC cell proliferation and the related mechanism both in vitro and in vivo. Our results found that the expression of KLF5, GCN5, GDF15, C5aR, and C5a was significantly upregulated in NSCLC patients. Mechanistic exploration in vitro revealed that C5a could facilitate A549 cell proliferation through increasing KLF5, GCN5, and GDF15 expression. Besides, KLF5 and GCN5 could form a complex, binding to GDF15 promoter in a KLF5-dependent manner and leading to GDF15 gene transcription. More importantly, GCN5-mediated KLF5 acetylation contributing to GDF15 gene transcription and cell proliferation upon C5a stimulation, the region (−103 to +58 nt) of GDF15 promoter which KLF5 could bind to, and two new KLF5 lysine sites (K335 and K391) acetylated by GCN5 were identified for the first time. Furthermore, our experiment in vivo demonstrated that the growth of xenograft tumors in BALB/c nude mice was greatly suppressed by the silence of KLF5, GCN5, or GDF15. Collectively, these findings disclose that C5a-driven KLF5–GCN5–GDF15 axis had a critical role in NSCLC proliferation and might serve as targets for NSCLC therapy.

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“…Also, its capacity to mobilize suppressive cells into the tumor microenvironment has been seen in genetically manipulated animals (34). The relevance of IL1b for cancer progression in humans has been demonstrated in melanoma (24) and non-small cell lung cancer (NSCLC) patients (35). The former study demonstrated that IL1b secreted by tumors carrying the BRAF mutation V600E promotes a PD-1 ligand-mediated suppressive effect in tumor-associated fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic Transformation Can Orchestrate Immune Evasion and Inflammation in Human Mesenchymal Stem Cells Independently of Extrinsic Immune-Selective Pressure

Miranda

Funes²,

Sánchez

et al. 2015

Cancer Research

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Immune escape is a hallmark of cancer, but whether it relies upon extrinsic immune-selective pressure or is inherently orchestrated by oncogenic pathways is unresolved. To address this question, we took advantage of an in vitro model of sequentially transformed human mesenchymal stem cells (hMSC). Neoplastic transformation in this model increased the natural immuneevasive properties of hMSC, both by reducing their immunogenicity and by increasing their capacity to inhibit mitogen-driven T-cell proliferation. We also found that IFNg signaling was globally affected in transformed hMSC. As a consequence, the natural inhibitory effect of hMSC on T-cell proliferation switched from an inducible mechanism depending on IFNg signaling and mediated by indoleamine 2,3-dioxygenase to a constitutive mechanism that relied upon IL1b involving both secreted and membraneexpressed molecules. After transformation, increased IL1b expression both sustained the immunosuppressive properties of hMSC and increased their tumorigenicity. Thus, in this model system, IL1b acted as intrinsic inflammatory mediator that exerted an autocrine influence on tumor growth by coordinately linking immune escape and tumorigenicity. Collectively, our findings show how oncogenes directly orchestrate inflammation and immune escape to drive the multistep process of cancer progression, independently of any need for immunoediting in the tumor microenvironment. Cancer Res; 75(15); 3032-42. Ó2015 AACR.

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IL-1β-Mediated Repression of microRNA-101 Is Crucial for Inflammation-Promoted Lung Tumorigenesis

Cited by 103 publications

References 48 publications

Neutrophil-Derived IL-1β Impairs the Efficacy of NF-κB Inhibitors against Lung Cancer

Neutrophil-Derived IL-1β Impairs the Efficacy of NF-κB Inhibitors against Lung Cancer

C5a induces A549 cell proliferation of non-small cell lung cancer via GDF15 gene activation mediated by GCN5-dependent KLF5 acetylation

Oncogenic Transformation Can Orchestrate Immune Evasion and Inflammation in Human Mesenchymal Stem Cells Independently of Extrinsic Immune-Selective Pressure

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