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Fgf8b Oncogene Mediates Proliferation and Invasion of Epstein–Barr Virus-Associated Nasopharyngeal Carcinoma Cells: Implication for Viral-Mediated Fgf8b Upregulation

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Fgf8b Oncogene Mediates Proliferation and Invasion of Epstein–Barr Virus-Associated Nasopharyngeal Carcinoma Cells: Implication for Viral-Mediated Fgf8b Upregulation Oncogene (2011) 30, 1518–1530 & 2011 Macmillan Publishers Limited All rights reserved 0950-9232/11 www.nature.com/onc ORIGINAL ARTICLE FGF8b oncogene mediates proliferation and invasion of Epstein–Barr virus-associated nasopharyngeal carcinoma cells: implication for viral-mediated FGF8b upregulation VWY Lui1,7, DM-S Yau1,7, CS-F Cheung1, SCC Wong1, AK-C Chan2, Q Zhou1, EY-L Wong1, CPY Lau1, EKY Lam1, EP Hui1, B Hong1, CWC Hui1, AS-K Chan1, PKS Ng3, Y-K Ng4, K-W Lo5, CM Tsang6, SKW Tsui3, S-W Tsao6 and ATC Chan1 1State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong; 2Department of Pathology, Queen Elizabeth Hospital, Hong Kong; 3School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong; 4Department of Surgery, Chinese University of Hong Kong, Hong Kong; 5Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong and 6Department of Anatomy, University of Hong Kong, Hong Kong The fibroblast growth factor 8b (FGF8b) oncogene is identified LMP1 as the first viral oncogene capable of known to be primarily involved in the tumorigenesis and directly inducing FGF8b (an important cellular oncogene) progression of hormone-related cancers. Its role in other expression in human cancer cells. This novel mechanism of epithelial cancers has not been investigated, except for viral-mediated FGF8 upregulation may implicate a new esophageal cancer, in which FGF8b overexpression was role of oncoviruses in human carcinogenesis. mainly found in tumor biopsies of male patients. These Oncogene (2011) 30, 1518–1530; doi:10.1038/onc.2010.529; observations were consistent with previous findings in published online 29 November 2010 these cancer types that the male sex-hormone androgen is responsible for FGF8b expression. Nasopharyngeal Keywords: FGF8b; NPC; LMP1; NF-kB carcinoma (NPC) is a highly metastatic cancer of head and neck commonly found in Asia. It is etiologically associated with Epstein–Barr Virus (EBV) infection, inflammatory tumor microenvironment and relatively Introduction higher male predominance. Here, we reported for the first time that FGF8b is overexpressed in this EBV-associated Fibroblast growth factor 8b (FGF8b) is an oncogene non-hormone-related cancer of the head and neck, NPC. found to be predominantly overexpressed in hormone- More importantly, overexpression of FGF8b mRNA and related cancers, namely prostate and breast cancers protein was detected in a large majority of NPC tumors (Tanaka et al., 1998; Mattila and Harkonen, 2007). The from both male and female genders, in addition to multiple potent oncogenic activity of FGF8b has been demon- NPC cell lines. We hypothesized that FGF8b over- strated in vivo as FGF8b-overexpressing murine fibro- expression may contribute to NPC tumorigenesis. Using blasts causes transformation and rapid tumor formation EBV-associated NPC cell lines, we demonstrated that in nude mice (MacArthur et al., 1995a). Such a specific knockdown of FGF8b by small interfering RNA remarkable transforming ability of FGF8b was further inhibited cell proliferation, migration and invasion, demonstrated in transgenic mouse models overexpres- whereas exogenous FGF8b stimulated these multiple sing FGF8b. Transgenic mice overexpressing FGF8b phenotypes. Further mechanistic investigation revealed (under the control of the mouse mammary tumor virus that in addition to NF-jB signaling (a major inflamma- promoter, MMTV) frequently developed mammary tory signaling pathway known to be activated in NPC), an tumors with lung metastases, salivary gland tumors, important EBV oncoprotein, the latent membrane protein invasive lobular adenocarcinomas, as well as ductal 1 (LMP1), was found to be a direct inducer of FGF8b hyperplasia (Daphna-Iken et al., 1998). Similarly, tissue- overexpression in NPC cells, whereas androgen (testos- specific overexpression of FGF8b in the prostate terone) has minimal effect on FGF8b expression in EBV- epithelium of transgenic mice resulted in the develop- associated NPC cells. In summary, our study has ment of prostate neoplasia, stromal hyperplasia, pros- tate adenocarcinoma with lymph node metastasis (Song et al., 2002; Zhong et al., 2006). Consistent with these Correspondence: Dr ATC Chan or Dr VWY Lui, Department of findings, it has been demonstrated that FGF8b over- Clinical Oncology, The Chinese University of Hong Kong, Prince of expression in both prostate and breast cancer cells can Wales Hospital, Sha Tin, Hong Kong. promote tumor cell growth and formation in nude mice E-mails: [email protected] or [email protected] 7Denotes cofirst authorship (Song et al., 2000; Ruohola et al., 2001), whereas specific Received 11 March 2010; revised 15 October 2010; accepted 16 October downregulation of FGF8b by antisense RNA inhibited 2010; published online 29 November 2010 the in vivo tumorigenicity of prostate cancer cells FGF8b upregulation in NPC VWY Lui et al 1519 (Rudra-Ganguly et al., 1998). These cumulative evi- involved in the carcinogenesis of other human malig- dences establish the role of FGF8b in carcinogenesis of nancies, especially in those hormone-unrelated cancers. hormone-related cancers (Tanaka et al., 1998; Marsh Nasopharyngeal carcinoma (NPC) is a highly invasive et al., 1999; Gnanapragasam et al., 2003). and metastatic head and neck cancer commonly found in FGF8b is a member of a large family of FGF8 Asia with a high incidence rate of 15–50/100 000 persons/ (previously known as the androgen-induced growth year (comparable with that of pancreatic cancer in the factor, AIGF). FGF8 is known to be essential for US) (Chan et al., 2002; Spano et al., 2003; Anderson embryogenesis (Crossley and Martin, 1995), in particu- et al., 2006). In endemic regions, NPC is characterized by lar, for the development/organogenesis of the cranio- its strong etiologic association with Epstein–Barr virus facial, pharyngeal, brain, cardiac, kidney, urogenital infection (EBV, a known oncogenic virus), high meta- organs and limbs (Heikinheimo et al., 1994; Crossley static potential (Skinner et al., 1991), highly inflamma- et al., 1996; Mattila and Harkonen, 2007). Investigation tory tumor microenvironment with heavy lymphocyte on the involvement of FGF8b in hormone-related infiltration (Lo and Huang, 2002), as well as a male cancers was indeed based on the initial discovery of predominance of 3:1 (Bhattacharyya, 2004). It is believed FGF8 (androgen-induced growth factor) in an andro- that NPC occurs as a result of complex interplay of local gen-dependent mouse mammary carcinoma cell line factors in the nasopharynx, EBV and the inflammatory (Tanaka et al., 1992) and detection of FGF8 over- tumor microenvironment. The molecular mechanisms expression in human breast and prostate cancers underlying its highly invasive and metastatic nature, as (Tanaka et al., 1995; Leung et al., 1996; Gnanapraga- well as the reported male predominance are not fully sam et al., 2002). Further genomic and functional understood. Here, we reported for the first time that characterization of the FGF8 family demonstrated that FGF8b is overexpressed in this EBV-associated non- the FGF8b isoform (one of the four human FGF8 hormone-related cancer of the head and neck, NPC. isoforms: FGF8a, b, e and f (Gemel et al., 1996)) More importantly, overexpression of FGF8b mRNA possesses the greatest mitogenic and, more importantly, and protein was detected in a large majority of NPC the greatest transforming activity than the other iso- tumors from both male and female genders. We forms, both in vitro and in vivo (MacArthur et al., 1995a, hypothesized that FGF8b overexpression contributed 1995b; Blunt et al., 1997; Song et al., 2000; Olsen et al., to NPC tumorigenesis. In addition to the identification 2006). It is believed that FGF8b is one of the most of NF-kB-mediated FGF8b upregulation in EBV- important FGF8 isoforms in human carcinogenesis associated NPC cells, this mechanistic investigation has (Marsh et al., 1999; Gnanapragasam et al., 2003), also identified latent membrane protein 1 (LMP1) as the although the exact physiological function of each first viral oncogene capable of directly inducing FGF8b isoform is yet-to-be fully revealed. (an important cellular oncogene) expression in human Owing to the original discovery of FGF8 in an cancer cells, which may reveal a new role of oncoviruses androgen-dependent system (Tanaka et al., 1992), as in human carcinogenesis. well as cumulative findings that FGF8b knockin mice developed prostate and breast cancers, investigations on the role of FGF8b in human oncogenesis have primarily Results been focused on hormone-related cancers. Clinical studies revealed that FGF8b overexpression was found FGF8b overexpression in NPC biopsies and cell lines in the majority of prostate cancer (40–80%) (Dorkin To investigate the possible involvement of FGF8b in et al., 1999; Gnanapragasam et al., 2002, 2003; Tanaka NPC tumorigenesis, we first examined the expression of et al., 2002; Zhong et al., 2006) and breast cancer (B70– FGF8b mRNA in 26 NPC tumor biopsies (18 from 100%) (Marsh et al., 1999). Moreover, its overexpres- males and 8 from females) by reverse transcriptase–PCR sion was clinically associated with disease progression (RT–PCR). Normal human colon epithelial tissues (as (mainly staging and grading), poor prognosis, poor well as a normal esophageal epithelial control cell line, survival (Dorkin et al., 1999; Valve et al., 2001), and Het-1A; ATCC, Manassas,
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