title: Interleukin-17 produced by tumor microenvironment promotes self-renewal of CD133+ cancer stem-like cells in ovarian cancer.
abstract: 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(+) cancer stem-like cells (CSLCs). We detected IL-17-producing cells (CD4(+) cells and CD68(+) macrophages) in the niche of CD133(+)CSLCs. Meanwhile, there was IL-17 receptor expression on CD133(+)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(+)CSLCs were significantly enhanced in a dose-dependent manner. Moreover, ovarian CD133(+)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(+)CSLCs. Further investigation through gene profiling revealed that the stimulation function of IL-17 on self-renewal of ovarian CD133(+)CSLCs might be mediated by the nuclear factor (NF)-κB and p38 mitogen-activated protein kinases (MAPK) signaling pathway. NF-κB and p38 MAPK were activated by IL-17. More importantly, IL-17-promoted self-renewal was inhibited by specific inhibitors of NF-κB and p38 MAPK. Taken together, our data indicate that IL-17 contributed to ovarian cancer malignancy through promoting the self-renewal of CD133(+)CSLCs and that IL-17 and its signaling pathway might serve as therapeutic targets for the treatment of ovarian cancer.
authors.affiliation: Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: T
authors.initials: T
authors.lastname: Xiang
authors.affiliation: Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: H
authors.initials: H
authors.lastname: Long
authors.affiliation: Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: L
authors.initials: L
authors.lastname: He
authors.affiliation: Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: X
authors.initials: X
authors.lastname: Han
authors.affiliation: Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: K
authors.initials: K
authors.lastname: Lin
authors.affiliation: Department of Obstetrics and Gynecology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: W
authors.initials: W
authors.lastname: Zhuo
authors.affiliation: 1] Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China [2] Department of Obstetrics and Gynecology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: R
authors.initials: R
authors.lastname: Xie
authors.affiliation: 1] Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China [2] Biomedical Analysis Center, Third Military Medical University, Chongqing, China.
authors.forename: B
authors.initials: B
authors.lastname: Zhu
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D006023:Glycoproteins / Q000096:biosynthesis / Q000276:immunology; D064593:Heterografts; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000276:immunology* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D010455:Peptides / Q000276:immunology; D014162:Transfection; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; D020381:Interleukin-17; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse