FGF8b oncogene mediates proliferation and invasion of Epstein–Barr virus-associated nasopharyngeal carcinoma cells: implication for viral-mediated FGF8b upregulation

Abstract

The fibroblast growth factor 8b (FGF8b) oncogene is known to be primarily involved in the tumorigenesis and progression of hormone-related cancers. Its role in other epithelial cancers has not been investigated, except for esophageal cancer, in which FGF8b overexpression was mainly found in tumor biopsies of male patients. These observations were consistent with previous findings in these cancer types that the male sex-hormone androgen is responsible for FGF8b expression. Nasopharyngeal 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 higher male predominance. Here, we reported for the first time that FGF8b is overexpressed in this EBV-associated non-hormone-related cancer of the head and neck, NPC. More importantly, overexpression of FGF8b mRNA and protein was detected in a large majority of NPC tumors from both male and female genders, in addition to multiple NPC cell lines. We hypothesized that FGF8b overexpression may contribute to NPC tumorigenesis. Using EBV-associated NPC cell lines, we demonstrated that specific knockdown of FGF8b by small interfering RNA inhibited cell proliferation, migration and invasion, whereas exogenous FGF8b stimulated these multiple phenotypes. Further mechanistic investigation revealed that in addition to NF-jB signaling (a major inflammatory signaling pathway known to be activated in NPC), an important EBV oncoprotein, the latent membrane protein 1 (LMP1), was found to be a direct inducer of FGF8b overexpression in NPC cells, whereas androgen (testosterone) has minimal effect on FGF8b expression in EBVassociated NPC cells. In summary, our study has identified LMP1 as the first viral oncogene capable of directly inducing FGF8b (an important cellular oncogene) expression in human cancer cells. This novel mechanism of viral-mediated FGF8 upregulation may implicate a new role of oncoviruses in human carcinogenesis.

Enhanced Antitumor Activity with Combining Effect of mTOR Inhibition and Microtubule Stabilization in Hepatocellular Carcinoma

“…Immunohistochemistry was performed as previously described [30]. Tumor microvessels were stained with a rabbit anti-CD34 antibody (1 : 100 dilution, Santa Cruz Biotechnology).…”

NF-κB-mediated transcriptional upregulation of TNFAIP2 by the Epstein–Barr virus oncoprotein, LMP1, promotes cell motility in nasopharyngeal carcinoma

“…It possesses the ability to transform primary B lymphocytes 13 and rodent fibroblasts, 14 and it contributes to NPC development through cell proliferation, antiapoptosis, cell migration, invasion and angiogenesis. [15][16][17][18] Tumor necrosis factor a-induced protein 2 (TNFAIP2, also called B94 or M-sec) was originally identified as a TNFa-inducible gene in endothelial cells. 19 It was subsequently shown to be induced in an in vitro model of angiogenesis, 19 suggesting that it has an angiogenic role.…”

STGC3 inhibits xenograft tumor growth of nasopharyngeal carcinoma cells by altering the expression of proteins associated with apoptosis

“…The tumor suppressor genes p16/MTS1 , DLC1, CDH4, IGFBP-6 and DAB2 show homozygous deletions or reduced expression in NPC tissue (Lo et al , 1995; Sun et al , 1995; Kuo et al , 2010; Tong et al , 2010; Du et al , 2011; Low et al , 2011). Over-expression of the MYC , RAS, EZH2, FGF8b oncogenes has also been detected in some NPC tumors (Porter et al , 1994; Lu et al , 2011; Lui et al , 2011). Furthermore, loss of heterozygosity (LOH) studies have shown that NPC tumors contain deletions on chromosomal arms that include 3p, 9p and 11q (Huang et al , 1994; Hu et al , 1996; Hui et al , 1996).…”