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Cancer Stem-Like Cells in Ovarian Cancer Oncogene (2015) 34, 165–176 & 2015 Macmillan Publishers Limited All rights reserved 0950-9232/15 www.nature.com/onc ORIGINAL ARTICLE Interleukin-17 produced by tumor microenvironment promotes self-renewal of CD133 þ cancer stem-like cells in ovarian cancer T Xiang1,5, H Long1,5,LHe1, X Han1, K Lin1, Z Liang2, W Zhuo1, R Xie1,3 and B Zhu1,4 Inflammatory cytokines, components of cancer stem cells (CSCs) niche, could affect the characteristics of CSCs such as self-renewal and metastasis. Interleukin-17 (IL-17) is a new pro-inflammatory cytokine mainly produced by T-helper (Th17) cells and macrophages. The effects of IL-17 on the characteristics of CSCs remain to be explored. Here we first demonstrated a role of IL-17 in promoting the self-renewal of ovarian CD133 þ cancer stem-like cells (CSLCs). We detected IL-17-producing cells (CD4 þ cells and CD68 þ macrophages) in the niche of CD133 þ CSLCs. Meanwhile, there was IL-17 receptor expression on CD133 þ CSLCs derived from A2780 cell line and primary ovarian cancer tissues. By recombinant human IL-17 stimulation and IL-17 transfection, the growth and sphere formation capacities of ovarian CD133 þ CSLCs were significantly enhanced in a dose-dependent manner. Moreover, ovarian CD133 þ CSLCs transfected with IL-17 showed greater tumorigenesis capacity in nude mice. These data suggest that IL-17 promoted the self-renewal of ovarian CD133 þ CSLCs. Further investigation through gene profiling revealed that the stimulation function of IL-17 on self-renewal of ovarian CD133 þ CSLCs might be mediated by the nuclear factor (NF)-kB and p38 mitogen- activated protein kinases (MAPK) signaling pathway. NF-kB and p38 MAPK were activated by IL-17. More importantly, IL-17- promoted self-renewal was inhibited by specific inhibitors of NF-kB and p38 MAPK. Taken together, our data indicate that IL-17 contributed to ovarian cancer malignancy through promoting the self-renewal of CD133 þ CSLCs and that IL-17 and its signaling pathway might serve as therapeutic targets for the treatment of ovarian cancer. Oncogene (2015) 34, 165–176; doi:10.1038/onc.2013.537; published online 23 December 2013 Keywords: cancer stem cells; IL-17; self-renewal; ovarian cancer INTRODUCTION between CSCs niche and inflammation.10 Indeed, mounting Ovarian cancer is a complex tumor that displays cellular evidence has shown that chemokines and cytokines, such as 11 12 13 14 15 heterogeneity within the bulk tumor. Recent studies suggest that interleukin (IL)-1, IL-4, IL-6, IL-8, and IL-15, produced ovarian cancer contained a small subset of tumor cells with potent by CSCs itself or tumor microenvironment could exert tumorigenesis and stem cell-like properties, which are so-called direct effects on CSCs. However, the effect of inflammation on cancer stem cells (CSCs) or cancer stem-like cells (CSLCs).1–3 There CSCs characteristics in ovarian cancer remains to be detailed is now growing evidence that ovarian cancer, like many cancers, is explored. driven by CSCs.4 These cells are characterized by their self-renewal IL-17 is a newly identified pro-inflammatory cytokine that is þ capacity, multi-lineage differentiation properties and highly mainly produced by activated CD4 T-helper cells (also known as þ 16 oncogenic potential. Besides the capacity of tumorigenesis, Th17 cells), macrophages and CD8 T cells. Accumulating ovarian CSCs may mediate tumor metastasis and tumor relapses evidences have shown that IL-17-positive cells were frequently by virtue of their resistance to radio- and chemotherapies.5 Thus, involved in multiple inflammation-associated cancers, including 17 18 19,20 elucidating characteristics of ovarian CSCs is of great importance breast cancer, colorectal cancer, prostate cancer and 21,22 and may facilitate the development of novel agents targeting ovarian cancer. Although IL-17 may promote the growth of these cell populations. ovarian cancer, little is known about the specific biological Substantial evidences have suggested that CSCs were regulated mechanisms through which IL-17 contributes to ovarian cancer by intrinsic cellular pathways6 as well as extrinsic signals initiation or progression. In other cancers, it has been suggested generated by the tumor microenvironment. Cancer-related that IL-17 contributed to tumor malignancy by promoting inflammation is the hallmark of tumor microenvironment and capabilities of chemoresistance, angiogenesis and invasion of has powerful effects on tumor development.7 The tumor cancer cells.23 Interestingly, these cellular behaviors induced by microenvironment in which ovarian cancer develops has been IL-17 were also characteristics of CSCs, suggesting that IL-17 described as one enriched with a broad spectrum of pro- may contribute to the development of CSCs. Taken together, inflammatory cytokines and chemokines, which have been these data suggest that the role of IL-17 signaling in ovarian shown to influence clinical disease status and prognosis.8,9 cancer should be evaluated in the subpopulation of the ovarian Recent studies have shown that there may be a direct link CSCs. 1Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China; 2Department of Obstetrics and Gynecology, Southwest Hospital, Third Military Medical University, Chongqing, China; 3Department of Obstetrics and Gynecology, Xinqiao Hospital, Third Military Medical University, Chongqing, China and 4Biomedical Analysis Center, Third Military Medical University, Chongqing, China. Correspondence: Dr R Xie, Department of Obstetrics and Gynecology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China or Dr Professor B Zhu, Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China. E-mail: [email protected] or [email protected] 5These authors contributed equally to this work. Received 10 June 2013; revised 12 October 2013; accepted 1 November 2013; published online 23 December 2013 IL-17 promotes self-renewal of CD133 þ CSLCs T Xiang et al 166 IL-17 signaling is transduced by IL-17 receptor (IL-17R), which (Figure 2e), indicating that IL-17 was expressed in the niche of activates the transcription factor nuclear factor (NF)-kB. However, CSCs in ovarian cancer. Collectively, we found that IL-17- albeit weakly, IL-17R signaling can also be transduced by p38 producing cells locate in the niche of CSCs in ovarian cancer MAPK, resulting in the activation of a potential molecular AP1 tissues, suggesting the potential role of IL-17 on CD133 þ CSLCs in bridge between inflammation and cancer.24–27 Interestingly, these ovarian cancer. two signaling pathways are involved in the self-renewal of normal 28,29 stem cells and CSCs. Together, based on these evidences, we IL-17 promotes ovarian CD133 þ CSLCs self-renewal in vitro aimed to investigate the effect of IL-17 on the ovarian CSCs and the underlying mechanisms. Self-renewal is the most important characteristic of CSCs. And, NF-kB and MAPK, which could be activated by IL-17/IL-17R signaling, are involved in self-renewal of stem cells and CSCs.28,29 Thus, we hypothesized that IL-17 might promote self-renewal of ovarian RESULTS þ 1,3 þ CD133 CSLCs. Sphere formation reflects stem cell self-renewal. Expression of IL-17R on the ovarian CD133 CSLCs We first dissociated A2780-derived CD133 þ CSLCs spheres into It is known that inflammatory cytokines are components of CSCs 100 cells and stimulated cells with different concentrations of niche. Thus, we first used the human inflammatory response PCR recombinant human IL-17 (rhIL-17) (25, 50, 75, 100, 250, 500, 750 array to analyze the gene expression of inflammation-associated and 1000 ng/ml). After incubation for 7 days, the number of newly þ genes in A2780-derived ovarian CD133 CSLCs, which have been formed spheres were counted. As shown in Figure 3a, the number proved to be CSCs characteristics including self-renewal, multi- of spheres significantly increased by rhIL-17 stimulation from lineage differentiation properties and highly oncogenic potential concentrations of 25–250 ng/ml (P 0.01) when compared with 30 o in our previous study. Differences in gene expression profiles IL-17-untreated group, and the sphere number reached the þ between the A2780-derived ovarian CD133 CSLCs and non- maximum at 250 ng/ml. Then we dissociated A2780-derived À CSLCs (CD133 A2780 cells) were compared. Figure 1a shows the CD133 þ CSLCs spheres into 1, 10 and 100 cells and treated with þ scatter plot of expression level of each gene in ovarian CD133 250 ng/ml of rhIL-17 for 7 days. Similarly, treatment with rhIL-17 CSLCs and non-CSLCs. Interestingly, expression levels of many significantly increased the number of spheres (Po0.01; Figures 3b inflammation cytokines and their receptors were upregulated in and c). In addition, the effect of rhIL-17 was blocked by an IL-17R- þ the A2780-derived ovarian CD133 CSLCs (Figure 1b and neutralizing antibody at the concentration of 100 ng/ml (Po0.01; Supplementary Table 2). Some of them (such as IL-1R, IL-4R, Figure 3d and Supplementary Figure S1A). Importantly, similar 11–14 IL-6R and IL-8) were previous reported, whereas some of results were obtained in ovarian CD133 þ CSLCs derived from them were newly observed. Notably, the expression of IL-17R in ovarian tumor tissues (P 0.01, Figures 3e and f). In contrast to its þ o A2780-derived ovarian CD133 CSLCs was first observed. effects on CD133 þ CSLCs, rhIL-17 did not have any effect on the Expression of IL-17R was further verified by flow cytometric proliferation capacity of CD133-negative cells (non-CSLCs) analysis and immunofluorescence assay. As shown by flow (P40.05; Supplementary Figure S1B). However, CD133 þ CSLCs cytometric analysis, the percentage of IL-17R-expressing cells in percentage increased threefold more than control group in the þ the A2780-derived ovarian CD133 CSLCs was 73.80 þ 9.36%, serum-free culture medium when 100 ng/ml rhIL-17 was added in whereas it was just 24.30±3.4% in non-CSLCs, at the individual the culture medium (Po0.05; Figure 3g).
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