title: Antitumor effects of interleukin-6 (IL-6)/interleukin-6 receptor (IL-6R) signaling pathway inhibition in clear cell carcinoma of the ovary.
abstract: Among epithelial ovarian cancers, clear cell carcinoma of the ovary (CCC) has unique clinical and molecular characteristics that include chemoresistance resulting in poor prognosis. It was shown that CCC recently was characterized by specific upregulation of the IL-6/IL-6R-signal transducer and activator of transcription 3 (Stat3) signaling pathway. In this study, we aim to clarify whether IL-6/IL-6R mediated signaling pathway could have clinical relations with CCC and to evaluate inhibitory effects of the pathway on CCC carcinogenesis. A total of 84 CCC cases collected from primary surgical specimens were evaluated by the immunohistochemical analysis for IL-6R and phosphorylated Stat3 (pStat3), and we found that high IL-6R expression correlated with poor patient survival both by the univariate and multivariate analyses, suggesting that IL-6/IL-6R signaling pathway could be implicated in the progression of CCC. We further investigated the effects of IL-6/IL-6R mediated signaling pathway inhibition either by IL-6R small interfering RNA (siRNA) approach or humanized anti-human IL-6R antibody (tocilizumab) in CCC. Inhibition of endogenous IL-6R including tocilizumab in CCC cells did reduce cell invasion ability and restored their response to cytotoxic reagent. These data suggest that IL-6/IL-6R signaling pathway could act on CCC cells to enhance invasion and chemoresistance and, therefore, targeting IL-6/IL-6R mediated signaling pathway could be a promising therapeutic strategy for CCC.
authors: Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan.
authors: Nozomu
authors: N
authors: Yanaihara
authors: Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan.
authors: Yukihiro
authors: Y
authors: Hirata
authors: Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan.
authors: Noriko
authors: N
authors: Yamaguchi
authors: Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan.
authors: Yukiko
authors: Y
authors: Noguchi
authors: Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan.
authors: Misato
authors: M
authors: Saito
authors: Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan.|Department of Education for Clinical Research, National Center for Child Health and Development, Tokyo, Japan.
authors: Chie
authors: C
authors: Nagata
authors: Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan.
authors: Satoshi
authors: S
authors: Takakura
authors: Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan.
authors: Kyosuke
authors: K
authors: Yamada
authors: Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan.
authors: Aikou
authors: A
authors: Okamoto
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D011379:Prognosis; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C508600:IL6 protein, human; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C502936:tocilizumab
keywords: IL-6; IL-6R; Stat3; clear cell carcinoma of the ovary; tocilizumab