Interleukin 17A Promotes Hepatocellular Carcinoma Metastasis via NF-kB Induced Matrix Metalloproteinases 2 and 9 Expression

Li, Jianjun; Lau, G; Chen, Leilei; Dong, Sui Sui; Lan, Hui‐Yao; Huang, Xiao Ru; Li, Yan; Luk, John M.; Yuan, Yufeng; Guan, Xin Yuan

doi:10.1371/journal.pone.0021816

Cited by 180 publications

(183 citation statements)

References 44 publications

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“…A recent study also found that high expression of IL-17 and IL-17RE associated with poor prognosis of hepatocellular carcinoma (28). IL-17A has also been found to promote hepatocellular carcinoma metastasis via MMP2 and 9 expression (29).…”

Section: Discussionmentioning

confidence: 89%

IL-17A Produced by γδ T Cells Promotes Tumor Growth in Hepatocellular Carcinoma

et al. 2014

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Interleukin (IL)-17A is expressed in the tumor microenvironment where it appears to contribute to tumor development, but its precise role in tumor immunity remains controversial. Here, we report mouse genetic evidence that IL-17A is critical for tumor growth. IL-17A-deficient mice exhibited reduced tumor growth, whereas systemic administration of recombinant mouse IL-17A promoted the growth of hepatocellular carcinoma. The tumor-promoting effect of IL-17A was mediated through suppression of antitumor responses, especially CD8 þ Tcell responses. Furthermore, we found that IL-17A was produced mainly by Vg4 gd T cells, insofar as depleting Vg4 gd T cells reduced tumor growth, whereas adoptive transfer of Vg4 gd T cells promoted tumor growth. Mechanistic investigations showed that IL-17A induced CXCL5 production by tumor cells to enhance the infiltration of myeloid-derived suppressor cells (MDSC) to tumor sites in a CXCL5/CXCR2-dependent manner. IL-17A also promoted the suppressive activity of MDSC to reinforce suppression of tumoral immunity. Moreover, we found that MDSC could induce IL-17A-producing gd T cells via production of IL-1b and IL-23. Conversely, IL-17A could also enhance production of IL-1b and IL-23 in MDSC as a positive feedback. Together, our results revealed a novel mechanism involving cross-talk among gd T cells, MDSCs, and tumor cells through IL-17A production. These findings offer new insights into how IL-17A influences tumor immunity, with potential implications for the development of tumor immunotherapy. Cancer Res; 74(7); 1969-82. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 89%

IL-17A Produced by γδ T Cells Promotes Tumor Growth in Hepatocellular Carcinoma

et al. 2014

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“…Recent studies have shown that IL-17A stimulates tumor progression and metastasis in several tumor types (36)(37)(38). Although most CT-26 cells contain IL-17A receptor a (IL-17RA; ref.…”

Section: Il-17a Promotes Intravasation Of Cancer Cellsmentioning

confidence: 99%

Interleukin-17A Modulates Circulating Tumor Cells in Tumor Draining Vein of Colorectal Cancers and Affects Metastases

Tseng

Yang

Liang

et al. 2014

Clinical Cancer Research

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Purpose: Metastasis is the major cause of death in patients with colorectal cancer (CRC). Circulating tumor cells (CTC) are believed to cause metastasis and serve as a prognostic marker for mortality in clinical stage IV patients. However, most studies are conducted in late-stage cases when distant metastases have already occurred; thus, such results provide limited clinical use. This study focused on whether CTCs can predict the risk of metastasis after treatment of the primary tumor in early-stage patients with CRC.Experimental Design: CTCs were quantified using EpCAM-positive/CD45-negative immunoselection and flow cytometry in patients with CRC. A mouse model was used to investigate the mechanistic roles of CTCs and interleukin (IL)-17A in metastasis.Results: The number of mesenteric CTCs obtained from stage II patients was higher than that obtained from patients in stages I, III, and IV. In addition, following invasion of orthotopically implanted tumors in our mouse model, we found that CTCs exhibited an increase-then-decrease pattern, accompanied by corresponding changes in serum IL-17A levels and opposing changes in serum granulocyte macrophage colony-stimulating factor (GM-CSF) levels. Ablation of IL-17A and administration of rGM-CSF effectively suppressed the increase in CTCs and prevented metastasis in mice. Moreover, IL-17A promoted cancer cell motility, matrix digestion, and angiogenesis, whereas GM-CSF stimulated the elimination of CTCs by boosting host immunity. Notably, serum levels of IL-17A were also correlated with disease-free survival in patients with CRC.Conclusions: Our results showed that CTCs and IL-17A could serve as prognostic markers and therapeutic targets for CRC metastasis. Clin Cancer Res; 20(11); 2885-97. Ó2014 AACR.

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“…IL-17 enhances MMP-9 expression and lung tumor cell motility. IL-17 can stimulate expression of MMP-9 (1,18,36), and this may partially account for the selective stimulation of lung tumor growth in vivo. Consequently, we evaluated gelatinase activity in the BAL fluid from adenovirus-treated mice by zymography.…”

Section: Il-17 Overexpression Increases Lung Tumor Growth In K-mentioning

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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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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Interleukin 17A Promotes Hepatocellular Carcinoma Metastasis via NF-kB Induced Matrix Metalloproteinases 2 and 9 Expression

Cited by 180 publications

References 44 publications

IL-17A Produced by γδ T Cells Promotes Tumor Growth in Hepatocellular Carcinoma

IL-17A Produced by γδ T Cells Promotes Tumor Growth in Hepatocellular Carcinoma

Interleukin-17A Modulates Circulating Tumor Cells in Tumor Draining Vein of Colorectal Cancers and Affects Metastases

Promotion of lung tumor growth by interleukin-17

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