title: Cytokine gene expression signature in ovarian clear cell carcinoma.
abstract: Cytokine expression in a tumor microenvironment can impact both host defense against the tumor and tumor cell survival. In this study, we sought to clarify whether the cytokine gene expression profile could have clinical associations with ovarian cancer. We analyzed the expression of 16 cytokine genes (IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p35, IL-12p40, IL-15, IFN-γ, TNF-α, IL-6, HLA-DRA, HLA-DPA1 and CSF1) in 50 ovarian carcinomas. Hierarchical clustering analysis of these tumors was carried out using Cluster software and differentially expressed genes were examined between clear cell carcinoma (CCC) and other subtypes. Following this examination we evaluated the biological significance of IL-6 knockdown in CCC. Unsupervised hierarchical clustering analysis of cytokine gene expression revealed two distinct clusters. The relationship between the two clusters and clinical parameters showed statistically significant differences in CCC compared to other histologies. CCC showed a dominant Th-2 cytokine expression pattern driven largely by IL-6 expression. Inhibition of IL-6 in CCC cells suppressed Stat3 signaling and rendered cells sensitive to cytotoxic agents. The unique cytokine expression pattern found in CCC may be involved in the pathogenesis of this subtype. In particular, high IL-6 expression appears likely to be driven by the tumor cells, fueling an autocrine pathway involving IL-6 expression and Stat3 activation and may influence survival when exposed to cytotoxic chemotherapy. Modulation of IL-6 expression or its related signaling pathway may be a promising strategy of treatment for CCC.
authors: Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan. yanazou@jikei.ac.jp
authors: Nozomu
authors: N
authors: Yanaihara
authors: Michael S
authors: MS
authors: Anglesio
authors: Kazunori
authors: K
authors: Ochiai
authors: Yukihiro
authors: Y
authors: Hirata
authors: Misato
authors: M
authors: Saito
authors: Chie
authors: C
authors: Nagata
authors: Yasushi
authors: Y
authors: Iida
authors: Satoshi
authors: S
authors: Takakura
authors: Kyosuke
authors: K
authors: Yamada
authors: Tadao
authors: T
authors: Tanaka
authors: Aikou
authors: A
authors: Okamoto
mesh_terms: D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics*; D005810:Multigene Family; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism; D010053:Ovary / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor / Q000096:biosynthesis / Q000378:metabolism; D018227:Sarcoma, Clear Cell / Q000235:genetics* / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human