title: Interleukin 6 promotes endometrial cancer growth through an autocrine feedback loop involving ERK-NF-κB signaling pathway.
abstract: Interleukin (IL)-6 as an inflammation factor, has been proved to promote cancer proliferation in several human cancers. However, its role in endometrial cancer has not been studied clearly. Previously, we demonstrated that IL-6 promoted endometrial cancer progression through local estrogen biosynthesis. In this study, we proved that IL-6 could directly stimulate endometrial cancer cells proliferation and an autocrine feedback loop increased its production even after the withdrawal of IL-6 from the medium. Next, we analyzed the mechanism underlying IL-6 production in the feedback loop and found that its production and IL-6-stimulated cell proliferation were effectively blocked by pharmacologic inhibitors of nuclear factor-kappa B (NF-κB) and extra-cellular signal-regulated kinase (ERK). Importantly, activation of ERK was upstream of the NF-κB pathways, revealing the hierarchy of this event. Finally, we used an orthotopic nude endometrial carcinoma model to confirm the effects of IL-6 on the tumor progression. Taken together, these data indicate that IL-6 promotes endometrial carcinoma growth through an expanded autocrine regulatory loop and implicate the ERK-NF-κB pathway as a critical mediator of IL-6 production, implying IL-6 to be an important therapeutic target in endometrial carcinoma.
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Che
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Bin-Ya
authors.initials: BY
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Fang-Yuan
authors.initials: FY
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yin-Yan
authors.initials: YY
authors.lastname: He
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liao
authors.affiliation: Department of Obstetrics and Gynecology, International Peace Maternity & Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: krisgu70@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital Affiliated to Tong Ji University, Shanghai, China. Electronic address: wanxp@sjtu.edu.cn.
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Wan
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016889:Endometrial Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D025461:Feedback, Physiological; D005260:Female; D064593:Heterografts; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D016328:NF-kappa B; D012333:RNA, Messenger; D012334:RNA, Neoplasm
keywords: Autocrine; Endometrial carcinoma; IL-6; Proliferation