Oncogenic Fli-1 is a potential prognostic marker for the progression of epithelial ovarian cancer

BMC Cancer

Wei Song³  Lingyun Hu²  Wei Li³  Guanjun Wang³  Yan Li³  Lei Yan³  Ailing Li¹  Jiuwei Cui³ 

[1] Institute of Basic Medical Sciences, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing 100850, China

[2] Obstetrics and Gynecology, the General Hospital of Chinese People’s Liberation Army, Beijing, China

[3] Cancer center, the First Hospital of Jilin University, 71 Xinmin Street, Changchun 130021, China

关键词: Overall survival;    Tumor stage;    Fli-1;    Epithelial ovarian cancer (EOC);   

Others  :  857296
DOI  :  10.1186/1471-2407-14-424

 received in 2013-09-21, accepted in 2014-05-29,  发布年份 2014

【 摘 要 】

Background

Ovarian cancer is the most lethal gynecologic malignancy, but its etiology remains poorly understood. This study investigated the role of Fli-1 in ovarian carcinogenesis and disease survival.

Methods

Fli-1 protein expression was evaluated by immunohistochemistry in 104 primary epithelial ovarian cancer (EOC) patients with known follow-up data and 20 controls. Correlation between Fli-1 expression and clinical characteristics was evaluated with the logistic regression. Kaplan Meier analysis was used to assess the impact of Fli-1 expression on overall survival (OS) and disease-free survival (DFS). Cell proliferation and migration assay were used to explore the function of Fli-1 in ovarian cancer cells.

Results

Fli-1 was expressed in 74% cases and up-regulated in EOC tissues compared with normal control tissues (p< 0.05). The high expression of Fli-1 was significantly associated with advanced tumor stage, positive lymph nodal involvement, and poor OS and DFS (p< 0.05). Further analysis showed Fli-1 is an independent prognostic factor for OS and DFS. Down-regulation of Fli-1 inhibited cell proliferation but did not affect cell migration in SKOV3 cells.

Conclusions

This study revealed that Fli-1 played an essential role in the development and progression of ovarian cancers. Its overexpression is intimately related to malignant phenotypes and poor clinical outcome, suggesting that Fli-1 is a potential prognostic marker and therapeutic molecular target in ovarian cancer.

【 授权许可】

   
2014 Song et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin 2011, 61:69-90.
• [2]Siegel R, Naishadham D, Jemal A: Cancer statistics. CA Cancer J Clin 2012, 62:10-29.
• [3]Onda T, Yoshikawa H: Neoadjuvant chemotherapy for advanced ovarian cancer: overview of outcomes and unanswered questions. Expert Rev Anticancer Ther 2011, 11:1053-1067.
• [4]Kurman RJ, Visvanathan K, Roden R, Wu TC, Shih IM: Early detection and treatment of ovarian cancer: shifting from early stage to minimal volume of disease based on a new model of carcinogenesis. Am J Obstet Gynecol 2008, 198:351-356.
• [5]Ben-David Y, Bernstein A: Friend virus-induced erythroleukemia and the multistage nature of cancer. Cell 1991, 66:831-834.
• [6]Klemsz MJ, Maki RA, Moore J, Hromas R: Characterization of the ets oncogene family member, fli-1. J Biol Chem 1994, 268:5769-5773.
• [7]Maroulakou IG, Bowe DB: Expression and function of Ets transcription factors in mammalian development: a regulatory network. Oncogene 2000, 19:6432-6442.
• [8]Oikawa T, Yamada T: Molecular biology of the Ets family of transcription factors. Gene 2003, 303:11-34.
• [9]Davidson B, Reich R, Goldberg I, Gotlieb WH, Kopolovic J, Berner A, Ben-Baruch G, Bryne M, Nesland JM: Ets-1 messenger RNA expression is a novel marker of poor survival in ovarian carcinoma. Clin Cancer Res 2001, 7:551-557.
• [10]Oikawa T: ETS transcription factors: possible targets for cancer therapy. Cancer Sci 2004, 95:626-633.
• [11]Melet F, Motro B, Rossi DJ, Zhang L, Bernstein A: Generation of a novel Fli-1 protein by gene targeting leads to a defect in thymus development and a delay in Friend virus-induced erythroleukemia. Mol Cell Biol 1996, 16:2708-2718.
• [12]Truong AH, Ben-David Y: The role of Fli-1 in normal cell function and malignant transformation. Oncogene 2000, 19:6482-6489.
• [13]Spyropoulos DD, Pharr PN, Lavenburg KR, Jackers P, Papas TS, Ogawa M, Watson DK: Hemorrhage, impaired hematopoiesis, and lethality in mouse embryos carrying a targeted disruption of the Fli1 transcription factor. Mol Cell Biol 2000, 20:5643-5652.
• [14]Liu F, Walmsley M, Rodaway A, Patient R: Fli1 acts at the top of the transcriptional network driving blood and endothelial development. Curr Biol 2008, 18:1234-1240.
• [15]Lakhanpal GK, Vecchiarelli-Federico LM, Li YJ, Cui JW, Bailey ML, Spaner DE, Dumont DJ, Barber DL, Ben-David Y: The inositol phosphatase SHIP-1 is negatively regulated by Fli-1 and its loss accelerates leukemogenesis. Blood 2010, 11:6428-6436.
• [16]Cui JW, Vecchiarelli-Federico LM, Li YJ, Wang GJ, Ben-David Y: Continuous Fli-1 expression plays an essential role in the proliferation and survival of F-MuLV-induced erythroleukemia and human erythroleukemia. Leukemia 2009, 23:1311-1319.
• [17]Erkizan HV, Uversky VN, Toretsky JA: Oncogenic partnerships: EWS-FLI1 protein interactions initiate key pathways of Ewing’s sarcoma. Clin Cancer Res 2010, 16:4077-4083.
• [18]Takigami I, Ohno T, Kitade Y, Hara A, Nagano1 A, Kawai G, Saitou M, Matsuhashi A, Yamada K, Shimizu K: Synthetic siRNA targeting the breakpoint of EWS/Fli-1 inhibits growth of Ewing sarcoma xenografts in a mouse model. Int J Cancer 2011, 128:216-226.
• [19]Zhang JJ, Guo HY, Zhang H, Wang HB, Qian GX XF, Hoffman AR, Hu JF, Ge S: Putative tumor suppressor miR-145 inhibits colon cancer cell growth by targeting oncogene Friend leukemia virus integration 1. Cancer 2011, 117:86-95.
• [20]Tamir A, Howard J, Higgins RR, Li YJ, Berger L, Zacksenhaus E, Reis M, Ben-David Y: Fli-1, an Ets-related transcription factor, regulates erythropoietin- induced erythroid proliferation and differentiation: evidence for direct transcriptional repression of the Rb gene during differentiation. Mol Cell Biol 1999, 19:4452-4464.
• [21]Yi H, Fujimura Y, Ouchida M, Prasad DD, Rao VN, Reddy ES: Inhibition of apoptosis by normal and aberrant Fli-1 and erg proteins involved in human solid tumors and leukemias. Oncogene 1997, 14:1259-1268.
• [22]Pereira R, Quang CT, Lesault I, Dolznig H, Beug H, Ghysdael J: FLI-1 inhibits differentiation and induces proliferation of primary erythroblasts. Oncogene 1999, 18:1597-1608.
• [23]Li YJ, Zhao X, Vecchiarelli-Federico LM, Li Y, Datti A, Cheng Y, Ben-David Y: Drug-mediated inhibition of Fli-1 for the treatment of leukemia. Blood Canc J 2012, 2:e54.
• [24]Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ: Cancer statistics, 2009. CA Cancer J Clin 2009, 59:225-249.
• [25]Goff BA, Mandel L, Muntz HG, Melancon CH: Ovarian carcinoma diagnosis. Cancer 2000, 89:2068-2075.
• [26]Ozols RF: Treatment goals in ovarian cancer. Int J Gynecol Cancer 2005, 15:S3-S11.
• [27]Kessler M, Fotopoulou C, Meyer T: The molecular fingerprint of high grade serous ovarian cancer reflects its fallopian tube origin. Int J Mol Sci 2013, 14:6571-6596.
• [28]Levanon K, Crum C, Drapkin R: Newinsights into the pathogenesis of serous ovarian cancer and its clinical impact. J Clin Oncol 2008, 26:5284-5293.
• [29]Bujor AM, Asano Y, Haines P, Lafyatis R, Trojanowska M: The C-ABL tyrosine kinase controls PKCδ induced Fli1 phosphorylation in human dermal fibroblasts. Arthritis Rheum 2011, 63:1729-1737.
• [30]Eisbacher M, Holmes ML, Newton A, Hogg PJ, Khachigian LM, Crossley M, Chong BH: Protein-protein interaction between Fli-1 and GATA-1 mediates synergistic expression of megakaryocyte-specific genes through cooperative DNA binding. Mol Cell Biol 2003, 23:3427-3441.
• [31]Starck J, Cohet N, Gonnet C, Sarrazin S, Doubeikovskaia Z, Doubeikovski A, Verger A, Duterque-Coquillaud M, Morle F: Functional cross-antagonism between transcription factors FLI-1 and EKLF. Mol Cell Biol 2003, 23:1390-1402.