Overexpression of proto-oncogene FBI-1 activates membrane type 1-matrix metalloproteinase in association with adverse outcome in ovarian cancers

Molecular Cancer

Research

Eric W-F Lam¹  Xiao-Feng Le²  Hextan YS Ngan³  Kar Fai Tam³  Oscar GW Wong⁴  Esther SY Wong⁴  Hoi Yan Chan⁴  Michelle KY Siu⁴  Annie NY Cheung⁴  LiLi Jiang⁵ 

[1] Cancer Research UK laboratories, Department of Surgery and Cancer, Imperial College London, London, UK;Department of Experimental Therapeutics, Division of Cancer Medicine, the University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA;Department of Obstetrics and Gynaecology, The University of Hong Kong, HKSAR, China;Department of Pathology and, The University of Hong Kong, HKSAR, China;Department of Pathology and, The University of Hong Kong, HKSAR, China;Department of Pathology, West China Hospital, Sichuan University, Chengdu, China;

关键词: Ovarian Cancer;    Ovarian Cancer Cell;    Ovarian Cancer Cell Line;    Borderline Tumor;    Malignant Ascites;   

DOI  :  10.1186/1476-4598-9-318

 received in 2010-07-02, accepted in 2010-12-21,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundFBI-1 (f actor that b inds to the i nducer of short transcripts of human immunodeficiency virus-1) is a member of the POK (POZ and Kruppel) family of transcription factors and play important roles in cellular differentiation and oncogenesis. Recent evidence suggests that FBI-1 is expressed at high levels in a subset of human lymphomas and some epithelial solid tumors. However, the function of FBI-1 in human ovarian cancers remains elusive.ResultsIn this study, we investigated the role of FBI-1 in human ovarian cancers, in particularly, its function in cancer cell invasion via modulating membrane type 1-matrix metalloproteinase (MT1-MMP). Significantly higher FBI-1 protein and mRNA expression levels were demonstrated in ovarian cancers samples and cell lines compared with borderline tumors and benign cystadenomas. Increased FBI-1 mRNA expression was correlated significantly with gene amplification (P = 0.037). Moreover, higher FBI-1 expression was found in metastatic foci (P = 0.036) and malignant ascites (P = 0.021), and was significantly associated with advanced stage (P = 0.012), shorter overall survival (P = 0.032) and disease-free survival (P = 0.016). In vitro, overexpressed FBI-1 significantly enhanced cell migration and invasion both in OVCA 420 and SKOV-3 ovarian carcinoma cells, irrespective of p53 status, accompanied with elevated expression of MT1-MMP, but not MMP-2 or TIMP-2. Moreover, knockdown of MT1-MMP abolished FBI-1-mediated cell migration and invasion. Conversely, stable knockdown of FBI-1 remarkably reduced the motility of these cells with decreased expression of MT1-MMP. Promoter assay and chromatin immunoprecipitation study indicated that FBI-1 could directly interact with the promoter spanning ~600bp of the 5'-flanking sequence of MT1-MMP and enhanced its expression in a dose-dependent manner. Furthermore, stable knockdown and ectopic expression of FBI-1 decreased and increased cell proliferation respectively in OVCA 420, but not in the p53 null SKOV-3 cells.ConclusionsOur results suggested an important role of FBI-1 in ovarian cancer cell proliferation, cell mobility, and invasiveness, and that FBI-1 can be a potential target of chemotherapy.

【 授权许可】

Unknown   
© Jiang et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.