Antitumor effects of interleukin-6 (IL-6)/interleukin-6 receptor (IL-6R) signaling pathway inhibition in clear cell carcinoma of the ovary

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 acti...

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Bibliographic Details
Published in:Molecular carcinogenesis 2016-05, Vol.55 (5), p.832-841
Main Authors: Yanaihara, Nozomu, Hirata, Yukihiro, Yamaguchi, Noriko, Noguchi, Yukiko, Saito, Misato, Nagata, Chie, Takakura, Satoshi, Yamada, Kyosuke, Okamoto, Aikou
Format: Article
Language:English
Subjects:
Adenocarcinoma, Clear Cell - genetics
Adenocarcinoma, Clear Cell - metabolism
Adenocarcinoma, Clear Cell - pathology
Antibodies, Monoclonal, Humanized - pharmacology
Antineoplastic Agents - pharmacology
Antitumor activity
Carcinogenesis
Cell Line, Tumor
Cell Movement - drug effects
Cell Proliferation - drug effects
Cell Survival - drug effects
Chemoresistance
Chemotherapy
clear cell carcinoma of the ovary
Cytokines
Cytotoxicity
Drug resistance
Female
Gene Expression Regulation, Neoplastic - drug effects
Humans
IL-6
IL-6R
Inhibition
Interleukin 6
Interleukin-6 - genetics
Interleukin-6 - metabolism
Kinases
Medical prognosis
Ovarian cancer
Ovarian Neoplasms - genetics
Ovarian Neoplasms - metabolism
Ovarian Neoplasms - pathology
Phosphorylation - drug effects
Prognosis
Receptors, Interleukin-6 - genetics
Receptors, Interleukin-6 - metabolism
Signal transduction
Signal Transduction - drug effects
siRNA
Stat3
Stat3 protein
STAT3 Transcription Factor - metabolism
tocilizumab
Transcription
Tumors
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Summary: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. © 2015 Wiley Periodicals, Inc.
ISSN:0899-1987
1098-2744
DOI:10.1002/mc.22325