Effects of IL-17A on the occurrence of lung adenocarcinoma

Liu, Ying; Cao, Zhen Yuan; Sun, Bo; Wang, Guang You; Fu, Zheng Qing; Liu, Yu Mei; Kong, Qing Fei; Wang, Jing-Hua; Zhang, Yao; Xu, Xin; Li, Hu Lun

doi:10.4161/cbt.12.7.16302

Cited by 41 publications

(31 citation statements)

References 18 publications

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“…Consequently, the ability of the activated IL-17 receptor to sequester SRSF1 (67) may be related to the opposing effects of IL-17 and p53 in MMP-9 regulation shown here. Consistent with our findings, prior studies have identified a protumorigenic role for IL-17 in models of lung adenocarcinoma (3,37,38,57). However, with one exception (3), these previous investigations did not examine the effects of IL-17A in an autochthonous lung tumor model and studies with tumor grafts have produced results that were often contradictory (40,72).…”

Section: Discussionsupporting

confidence: 76%

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Promotion of lung tumor growth by interleukin-17

Guenther

Pociask

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Recent findings demonstrate that inhaled cigarette smoke, the predominant lung carcinogen, elicits a T helper 17 (Th17) inflammatory phenotype. Interleukin-17A (IL-17), the hallmark cytokine of Th17 inflammation, displays pro-and antitumorigenic properties in a manner that varies according to tumor type and assay system. To investigate the role of IL-17 in lung tumor growth, we used an autochthonous tumor model (K-Ras LA1 mice) with lung delivery of a recombinant adenovirus that expresses IL-17A. Virus-mediated expression of IL-17A in K-Ras LA1 mice at 8 -10 wk of age doubled lung tumor growth in 3 wk relative to littermates that received a green fluorescent protein-expressing control adenovirus. IL-17 induced matrix metalloproteinase-9 (MMP-9) expression in vivo and in vitro. In accord with this finding, selective and specific inhibitors of MMP-9 repressed the increased motility and invasiveness of IL-17-treated lung tumor cells in culture. Knockdown or mutation of p53 promoted the motility of murine lung tumor cells and abrogated the promigratory role of IL-17. Coexpression of siRNAresistant wild-type, but not mutant, human p53 rescued both IL-17-mediated migration and MMP-9 mRNA induction in p53 knockdown lung tumor cells. IL-17 increased MMP-9 mRNA stability by reducing interaction with the mRNA destabilizing serine/arginine-rich splicing factor 1 (SRSF1). Taken together, our results indicate that IL-17 stimulates lung tumor growth and regulates MMP-9 mRNA levels in a p53-and SRSF1-dependent manner.

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Section: Discussionsupporting

confidence: 76%

“…Clinical findings with cancers of the stomach (78), prostate (59), colon (34), and lung (38) demonstrate that elevated levels of IL-17 correlate with a worse prognosis. However, in experimental models, the role of IL-17 in tumor growth depends on context.…”

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confidence: 99%

Promotion of lung tumor growth by interleukin-17

Guenther

Pociask

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…However, the role of the subset in lung cancer is somewhat controversial. Previous studies showed that a higher level of IL-17A mRNA and protein expression was noted in lung CD4+ T cells from NSCLC patients as compared to healthy controls [18,19]. Overexpression of IL-17 in tumor cell lines promotes angiogenesis and tumor growth when the tumors are implanted in immune-compromised mice [20].…”

Section: Discussionmentioning

confidence: 95%

Disturbed Th17/Treg Balance in Patients with Non-small Cell Lung Cancer

et al. 2015

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The fine balance of T help-17 (Th17)/regulatory T(Treg) cells is crucial for maintenance of immune homeostasis. However, there is little information concerning the role played in non-small cell lung cancer (NSCLC) by Th17/Treg cells. The objective of this study was to investigate the variation of Th17 and Treg cells in the peripheral blood of patients with NSCLC. Blood samples were collected from 19 patients with NSCLC and 19 healthy donors. Samples were processed to detect CD4(+)IL-17(+) Th17 cells and CD4(+)CD25(+)Foxp3(+) Treg cells by flow cytometry, and related gene expressions were assessed by real-time quantitative polymerase chain reaction. The concentrations of interleukin (IL)-1β, IL-6, IL-10, IL-17, IL-23, and transforming growth factor-beta (TGF-β1) were also measured by enzyme-linked immunosorbent assay analysis (ELISA). The frequency of circulating Th17 cells and Treg cells was increased in samples derived from patients with NSCLC, accompanied by the upregulation of Foxp3 and RORγt. However, a negative correlation between Treg cells and Th17 cells was found in patients with NSCLC. Additionally, the Th17/Treg ratio and the related cytokines were also significantly higher in patients with NSCLC than in healthy controls. Furthermore, the frequency of Th17 cells was positively correlated with IL-1β, IL-6, and IL-23 in patients with NSCLC, and the frequency of Treg cells was positively correlated with TGF-β1 and IL-10. More importantly, the Th17/Treg ratio was positively correlated with the CEA concentrations in patients with NSCLC. Our data indicated that Th17 and Treg subset are involved in the immunopathology of NSCLC. Distinct cytokine environment might play a key role in the differentiation of the Th17 and Treg cells in NSCLC. Reconstituting an adequate balance between Th17 and Treg may be beneficial in the treatment of NSCLC.

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“…Serum IL-17 and VEGF levels were found to be higher in patients with SCLC compared to healthy controls, and serum IL-17 turned out to be an unfavourable prognostic biomarker in patients with SCLC [54]. These data were supported by work showing IL-17A to facilitate angiogenesis in lung cancer cell lines [55], and high circulating levels of IL-17 in NSCLC patients to be an independent bad prognostic factor [56]. A similar study by Yu and colleagues confirmed that serum levels of IL-17 are elevated and can be used as an independent prognostic factor in NSCLC [57].…”

Section: Il-17 Prognostic and Predictive Value In Lung Cancermentioning

confidence: 56%

“…Additionally, higher levels of IL-17A were detected in serum of patients with lung adenocarcinoma compared to healthy controls, and higher IL-17A expression was found in lung adenocarcinoma tissue compared to neighbouring healthy lung tissue [55]. Likewise, Finotto and colleagues have determined that levels of IL-17A, RORα4 and RORC2 (the human homolog of RORγt) mRNA were also increased in NSCLC tumor tissue, along with elevated expression of FoxP3 mRNA [59].…”

Section: Il-17 Prognostic and Predictive Value In Lung Cancermentioning

confidence: 93%

The IL-17-Th1/Th17 pathway: an attractive target for lung cancer therapy?

Joerger

Finn

Cuffe

et al. 2016

Expert Opinion on Therapeutic Targets

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There is strong pharmaceutical development of agents targeting the IL-17-TH17 pathway for the treatment of psoriasis (Ps) and psoriatic arthritis (PsA). Lung cancer accounts for 28% of all cancer-related deaths worldwide, and roughly 80% of patients with newly-diagnosed non-small cell lung cancer (NSCLC) present with metastatic disease, with a poor prognosis of around 12 months. Therefore, there is a high unmet medical need for the development of new and potent systemic treatments in this deadly disease. The emergence of immunotherapies such as anti-PD-1 or anti-PDL1 as candidate therapies in non-small cell lung cancer (NSCLC) indicates that targeting critical immuno-modulatory cytokines including those within the IL-17-Th1/Th17 axis may have proven benefit in the treatment of lung cancer. Areas covered: In this review we describe the current evidence for aberrant IL-17-Th1/Th17 settings in cancer, particularly with regard to targeting this axis in NSCLC. We further discuss the current agents under pharmaceutical development which could potentially target this axis, and discuss the current limitations and areas of concern regarding the use of these in lung cancer. Expert opinion: Current evidence suggests that moving forward agents targeting the IL-17-Th1/Th17 pathway may have novel new oncoimmunology indications in the treatment paradigm for NSCLC.

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Effects of IL-17A on the occurrence of lung adenocarcinoma

Cited by 41 publications

References 18 publications

Promotion of lung tumor growth by interleukin-17

Promotion of lung tumor growth by interleukin-17

Disturbed Th17/Treg Balance in Patients with Non-small Cell Lung Cancer

The IL-17-Th1/Th17 pathway: an attractive target for lung cancer therapy?

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