Cytokine gene expression signature in ovarian clear cell carcinoma

Yanaihara,Nozomu; Anglesio,Michael  S.; Ochiai,Kazunori; Hirata,Yukihiro; Saito,Misato; Nagata,Chie; Iida,Yasushi; Takakura,Satoshi; Yamada,Kyosuke; Tanaka,Tadao; Okamoto,Aikou

doi:10.3892/ijo.2012.1533

Cytokine gene expression signature in ovarian clear cell carcinoma

Authors:
- Nozomu Yanaihara
- Michael S. Anglesio
- Kazunori Ochiai
- Yukihiro Hirata
- Misato Saito
- Chie Nagata
- Yasushi Iida
- Satoshi Takakura
- Kyosuke Yamada
- Tadao Tanaka
- Aikou Okamoto
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Affiliations: Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan, Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada
Published online on: June 26, 2012 https://doi.org/10.3892/ijo.2012.1533
Pages: 1094-1100

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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.

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1.	Vaughan S, Coward JI, Bast RC Jr, et al: Rethinking ovarian cancer: recommendations for improving outcomes. Nat Rev Cancer. 23:719–725. 2011. View Article : Google Scholar
2.	Köbel M, Kalloger SE, Boyd N, et al: Ovarian carcinoma subtypes are different diseases: implications for biomarker studies. PLoS Med. 5:e2322008.PubMed/NCBI
3.	Swenerton KD, Santos JL, Gilks CB, et al: Histotype predicts the curative potential of radiotherapy: the example of ovarian cancers. Ann Oncol. 22:341–347. 2010. View Article : Google Scholar : PubMed/NCBI
4.	Gilks CB, Ionescu DN, Kalloger SE, et al: Tumor cell type can be reproducibly diagnosed and is of independent prognostic significance in patients with maximally debulked ovarian carcinoma. Hum Pathol. 39:1239–1251. 2008. View Article : Google Scholar : PubMed/NCBI
5.	Anglesio MS, Carey MS, Köbel M, et al: Clear cell carcinoma of the ovary: A report from the first Ovarian Clear Cell Symposium, June 24th, 2010 (Review). Gynecol Oncol. 121:407–415. 2010. View Article : Google Scholar : PubMed/NCBI
6.	Takakura S, Takano M, Takahashi F, et al Japanese Gynecologic Oncology Group: Randomized phase II trial of paclitaxel plus carboplatin therapy versus irinotecan plus cisplatin therapy as first-line chemotherapy for clear cell adenocarcinoma of the ovary: a JGOG study. Int J Gynecol Cancer. 20:240–247. 2010. View Article : Google Scholar : PubMed/NCBI
7.	Shimada M, Kigawa J, Ohishi Y, et al: Clinicopathological characteristics of mucinous adenocarcinoma of the ovary. Gynecol Oncol. 113:331–334. 2009. View Article : Google Scholar : PubMed/NCBI
8.	Schreiber RD, Old LJ and Smyth MJ: Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion (Review). Science. 331:1565–1570. 2011.PubMed/NCBI
9.	Nelson BH: The impact of T-cell immunity on ovarian cancer outcomes (Review). Immunol Rev. 222:101–116. 2008. View Article : Google Scholar : PubMed/NCBI
10.	Kusuda T, Shigemasa K, Arihiro K, et al: Relative expression levels of Th1 and Th2 cytokine mRNA are independent prognostic factors in patients with ovarian cancer. Oncol Rep. 13:1153–1158. 2005.PubMed/NCBI
11.	Marth C, Fiegl H, Zeimet AG, et al: Interferon-gamma expression is an independent prognostic factor in ovarian cancer. Am J Obstet Gynecol. 191:1598–1605. 2004. View Article : Google Scholar : PubMed/NCBI
12.	Seike M, Yanaihara N, Bowman ED, et al: Use of a cytokine gene expression signature in lung adenocarcinoma and the surrounding tissue as a prognostic classifier. J Natl Cancer Inst. 99:1257–1269. 2007. View Article : Google Scholar : PubMed/NCBI
13.	Kurman RJ and Shih IeM: Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer - shifting the paradigm. Hum Pathol. 42:918–931. 2001. View Article : Google Scholar : PubMed/NCBI
14.	Bustin SA: Absolute quantification of mRNA using real-time reverse transcription polymerase chain reaction assays. J Mol Endocrinol. 25:169–193. 2000. View Article : Google Scholar : PubMed/NCBI
15.	Li N, Grivennikov SI and Karin M: The unholy trinity: inflammation, cytokines, and STAT3 shape the cancer microenvironment. Cancer Cell. 12:429–431. 2011. View Article : Google Scholar : PubMed/NCBI
16.	Itamochi H, Kigawa J and Terakawa N: Mechanisms of chemoresistance and poor prognosis in ovarian clear cell carcinoma (Review). Cancer Sci. 99:653–658. 2008. View Article : Google Scholar : PubMed/NCBI
17.	Tsiatas ML, Gyftaki R, Liacos C, et al: Study of T lymphocytes infiltrating peritoneal metastases in advanced ovarian cancer: associations with vascular endothelial growth factor levels and prognosis in patients receiving platinum-based chemotherapy. Int J Gynecol Cancer. 19:1329–1334. 2009. View Article : Google Scholar
18.	Tothill RW, Tinker AV, George J, et al: Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome. Clin Cancer Res. 14:5198–5208. 2008. View Article : Google Scholar : PubMed/NCBI
19.	Anglesio MS, George J, Kulbe H, et al: IL6-STAT3-HIF signaling and therapeutic response to the angiogenesis inhibitor sunitinib in ovarian clear cell cancer. Clin Cancer Res. 17:2538–2548. 2011. View Article : Google Scholar : PubMed/NCBI
20.	Yamaguchi K, Mandai M, Oura T, et al: Identification of an ovarian clear cell carcinoma gene signature that reflects inherent disease biology and the carcinogenic processes. Oncogene. 29:1741–1752. 2010. View Article : Google Scholar : PubMed/NCBI
21.	Hong DS, Angelo LS and Kurzrock R: Interleukin-6 and its receptor in cancer: implications for translational therapeutics (Review). Cancer. 110:1911–1928. 2007. View Article : Google Scholar : PubMed/NCBI
22.	Nilsson MB, Langley RR and Fidler IJ: Interleukin-6, secreted by human ovarian carcinoma cells, is a potent proangiogenic cytokine. Cancer Res. 65:10794–10800. 2005. View Article : Google Scholar : PubMed/NCBI
23.	Rabinovich A, Medina L, Piura B, Segal S and Huleihel M: Regulation of ovarian carcinoma SKOV-3 cell proliferation and secretion of MMPs by autocrine IL-6. Anticancer Res. 27:267–272. 2007.PubMed/NCBI
24.	Jones S, Wang TL, Shih IeM, et al: Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science. 330:228–231. 2010. View Article : Google Scholar : PubMed/NCBI
25.	Wiegand KC, Shah SP, Al-Agha OM, et al: ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med. 363:1532–1543. 2010. View Article : Google Scholar : PubMed/NCBI
26.	Cullen SJ, Ponnappan S and Ponnappan U: Catalytic activity of the proteasome fine-tunes Brg1-mediated chromatin remodeling to regulate the expression of inflammatory genes. Mol Immunol. 47:600–605. 2009. View Article : Google Scholar : PubMed/NCBI
27.	Wang Y, Niu XL, Qu Y, et al: Autocrine production of interleukin-6 confers cisplatin and paclitaxel resistance in ovarian cancer cells. Cancer Lett. 295:110–123. 2010. View Article : Google Scholar : PubMed/NCBI
28.	Guo Y, Nemeth J, O’Brien C, et al: Effects of siltuximab on the IL-6-induced signaling pathway in ovarian cancer. Clin Cancer Res. 16:5759–5769. 2010. View Article : Google Scholar : PubMed/NCBI
29.	Coward J, Kulbe H, Chakravarty P, et al: Interleukin-6 as a therapeutic target in human ovarian cancer. Clin Cancer Res. 17:6083–6096. 2011. View Article : Google Scholar : PubMed/NCBI