title: Non-CSCs nourish CSCs through interleukin-17E-mediated activation of NF-κB and JAK/STAT3 signaling in human hepatocellular carcinoma.
abstract: Within the cancer stem cell (CSC) niche, non-CSCs play an indispensable role in facilitating a microenvironment capable of maintaining CSC properties. Non-CSCs contribute to not only the structure and topology of the tumor microenvironment but also the maintenance of the dynamic state of CSCs. Interleukin-17E (IL-17E/IL-25) is important in allergic inflammation and protection against parasitic infection. Moreover, it has also been demonstrated that IL-17E takes part in different cancers recently. Here, for the first time we demonstrate that discrepant expression of IL-17E and the IL-17 receptor B (IL-17RB) exists in Nanog positive (Nanog(Pos)) CSCs and Nanog negative (Nanog(Neg)) non-CSCs in hepatocellular carcinoma (HCC). Moreover, we further demonstrate that IL-17E binding to IL-17RB activates NF-κB and JAK/Stat3 pathways to promote proliferation and sustain self-renewal of CSCs in HCC. Meanwhile, the beneficial effect of IL-17E on Nanog(Pos) CSCs could be blocked by specific inhibitors of JAK and NF-κB signaling. All the findings indicated that non-CSC-derived secreted IL-17E binds IL-17RB on CSCs to signal via JAK/Stat3 and NF-κB pathways to mediate crosstalk between CSCs and non-CSCs. Therefore, IL-17E/IL-17RB signaling represents a potential therapeutic target for treatment of HCC.
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Yongli
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Li
authors.initials: L
authors.lastname: Su
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Shan
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Huailong
authors.initials: H
authors.lastname: Xu
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Limei
authors.initials: L
authors.lastname: Liu
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Xuejiao
authors.initials: X
authors.lastname: Chen
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Chungang
authors.initials: C
authors.lastname: Liu
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Yao
authors.affiliation: School of Life Science, Zhejiang Sci-Tech University, Hangzhou, 310018, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Cheng
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China. Electronic address: junjiesh@gmail.com.
authors.forename: Junjie
authors.initials: J
authors.lastname: Shen
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China. Electronic address: cqian8634@gmail.com.
authors.forename: Cheng
authors.initials: C
authors.lastname: Qian
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics*; D053612:Janus Kinases / Q000096:biosynthesis / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics; D000071317:Nanog Homeobox Protein; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; D020381:Interleukin-17; C486780:NANOG protein, human; D016328:NF-kappa B; D000071317:Nanog Homeobox Protein; D053722:Receptors, Interleukin-17; D050796:STAT3 Transcription Factor; D053612:Janus Kinases
keywords: Cancer stem cell; Human hepatocellular carcinoma; IL-17E; IL-17RB; Non-cancer stem cell