FGF8 (fibroblast growth factor 8 (androgen-induced))
Written | 2011-03 | Mirjami Mattila, Pirkko Härkönen |
Department of Anatomy, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland |
(Note : for Links provided by Atlas : click)
1. Identity
Alias_names | General Information |
Alias_symbol (synonym) | AIGF |
Other alias | FGF-8 |
HBGF-8 | |
KAL6 | |
MGC149376 | |
HGNC (Hugo) | FGF8 |
LocusID (NCBI) | 2253 |
Atlas_Id | 40566 |
Location | 10q24.32 [Link to chromosome band 10q24] |
Location_base_pair | Starts at 101770130 and ends at 101776002 bp from pter ( according to hg19-Feb_2009) [Mapping FGF8.png] |
Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
2. DNA/RNA
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Figure 1. Exon representation of FGF8 isoforms (modified from Gemel et al., 1996). | |
Transcription | Alternative splicing of FGF8 gene gives rise to eight potential protein isoforms in the mouse (FGF8a-h) and four in the human (a, b, e, f) (Gemel et al., 1996, see Figure 1). |
3. Protein
Description | Fibroblast growth factor 8 is a secreted protein mitogen which belongs to fibroblast growth factor family. It exerts its action by binding cell surface tyrosine kinase recetors FGFR1-4 (Powers et al., 2000; Sleeman et al., 2001). It is implicated in embryonic development, tumor growth and angiogenesis. FGF8 was originally found as an androgen-induced growth factor (AIGF) from the conditioned medium of the androgen-dependent mouse mammary carcinoma cell line SC-3 (Tanaka et al., 1992). Whether its expression is directly androgen regulated is not clear (Gnanapragasam et al., 2002; Erdeich-Epstein et al., 2005). However, it has been shown to be co-expressed with androgen receptor in breast and prostate cancer. FGF8 is also called Kal-6 since it belongs to genes which have been shown to be mutated in a subset of patients with Kallman's syndrome (combination of hypogonadotropic hypogonadism and anosmia). In addition, FGF8 belongs to growth factors that could be isolated by affinity chromatography on Heparin-Sepharose columns and are thus called heparin-binding growth factors (HBGF). The interaction of heparin with FGF stabilizes FGF to denaturation (Gospodarowicz and Cheng, 1986) and proteolysis and is required for FGF mediated FGFR activation (Ornitz, 2000). |
Expression | In the adult human, FGF8 is expressed in kidney, testis, prostate, breast, peripheral blood leukocytes and in bone marrow (Ghosh et al., 1996; Marsh et al., 1999; Tanaka et al., 1998). However, during embryonal development, its expression is more widely distributed. The expression pattern of FGF8 during mouse embryonal development suggested roles for FGF8 in the morphogenesis of limbs, central nervous system and face, pharyngeal and cardiac systems, and the urogenital organs (Ohuchi et al., 1994; Heikinheimo et al., 1994; Crossley et al., 1996a; Crossley et al., 1996b; Haraguchi et al., 2000). Importantly, FGF8 expression is essential in gastrulation since homozygous loss of FGF8 leads to early embryonic lethality (Sun et al., 1999). Of the cancer cell lines, FGF8 expression has been detected in LNCaP, DU145, ALVA-31 and PC-3 prostate cancer cell lines, in MCF-7, ZR-75-1, T47-D, MDA-MB-231, SKBR-1, BT-549 and Hs578T breast cancer cell lines (Tanaka et al., 1995; Ghosh et al., 1996; Johnson et al., 1998; Marsh et al., 1999) and in UT-OV-2, UT-OV-4, UT-OV-5, UT-OV-6, UT-OV-10, UT-OV-11 and SK-OV-3 ovarian cancer cell lines (Valve et al., 2000). FGF8 has been shown to be expressed in benign breast and prostate lesions and in breast and prostate cancer (Leung et al., 1996; Tanaka et al., 1998; Dorkin et al., 1999). FGF8 expression is correlated with the expression of androgen receptor in both breast and prostate cancer (Wang et al., 1999; Tanaka et al., 2002). In prostate cancer the expression of FGF8 correlates with the poor prognosis (Dorkin et al., 1999). FGF8b is the primary isoform detected in breast cancer (Marsh et al., 1999) but in prostate cancer in addition to FGF8b, also FGF8a and FGF8e have been detected (Valve et al., 2001). Ovarian cancers of wide variety of histological types express FGF8 and its receptors and increased staining intensity of FGF8 has been associated with loss of differentiation within the tumors (Valve et al., 2000). |
Function | FGF receptors, to which FGF8 binds, are transmembrane proteins containing three extracellular immunoglobulin-like domains (IgI, IgII, IgIII), an acidic region between IgI and IgII, a transmembrane domain, and an intracellular tyrosine kinase domain. The involvement of receptor tyrosine phosphorylation in FGF signalling was first suggested by early binding studies (Moscatelli et al., 1987). An important mechanism by which FGF receptors determine specificity for different FGFs is by alternate exon usage of the IgIII forms. The exons coding for the three possible IgIII domains (IgIIIa, IgIIIb, IgIIIc) are situated contiguously and in the same order in FGFR1, FGFR2 and FGFR3 (Johnson et al., 1991; Chellaiah et al., 1994). The FGFR4 gene is unique in that there is only one possible form of its IgIII domain (Vainikka et al., 1992). IgIIIa splice variant codes for a secreted truncated protein which is not capable of transducing signals but instead may act to sequester released FGFs and potentially inhibit FGF signaling. FGF8 predominantly activates c-spliceforms of the receptors which are expressed mainly by the cells of mesenchymal origin. Thus, epithelially secreted FGF8 signals to neighbouring mesenchyme and may have a role in the epithelial-mesenchymal transition important in carcinogenesis. However, FGF8 is also well known as an autocrine growth factor in the stimulation of cancer cell proliferation, anchorage independent growth and migration (Figure 2). Full FGF receptor activation requires a coreceptor, a cell surface heparan sulfate proteoglycan (HSPG), which traps the growth factor on the cell surface and stabilizes the FGF/FGFR complex (Ornitz, 2000). Tissue-specific heparan fragments and tissue specific sulfation patterns of heparans may regulate FGFs by controlling their diffusion in the extracellular matrix and their ability to activate specific receptors (Chang et al., 2000). Strong binding of FGFs to heparin and heparan sulfated proteoglycans leads to deposition and sequestration of secreted or exocytosed FGFs in the extracellular matrix. Storage of FGFs in the extracellular matrix may serve as an angiogenesis regulatory reservoir released in response to degradation of the matrix (Folkman et al., 1988). FGF activation of FGFRs results in activation of signalling cascades such as phospholipase C gamma, phosphatidiylinositol-3 kinase and MAPK pathways that lead to expression of target genes and increased cell proliferation, survival and migration. Negative modulators of FGF signalling that have been found to be co-expressed with FGF8 include sprouty proteins (Spry1, Spry2), MAP-kinase phosphatase 3 (Mkp3) and Sef (Similar expression to FGFs) genes. Recently, FGF8 has been shown to downregulate the expression of thrombospondin-1 (TSP-1) (Mattila et al., 2006) through two independent pathways, MEK1/MEK2 and PI3K (Tarkkonen et al., 2010). Repression of TSP-1 may be an important mechanism involved in the induction of an angiogenic phenotype and growth of FGF8-expressing cancer. |
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Figure 2. Schematic view of the effects of FGF8 on tumor growth and progression. Morphological change in S115 breast cancer cells in vitro (up), induction of angiogenesis in nude mouse S115 tumors (middle, immunohistochemical staining for CD34), increase in nude mouse bone metastasis of MDA-MB-231 breast cancer cells (bottom, x-ray picture). | |
Homology | FGF8 has 70-80% amino acid sequence identity with FGF17 and FGF18. FGF8, FGF17 and FGF18 form FGF8 subfamily which has similar receptor binding properties and some overlapping sites of expression (Maruoka et al., 1998). |
4. Mutations
Note | Loss-of-function mutations of FGF8 are associated with isolated hypogonadotropic hypogonadism with variable sense of smell (Kallmann syndrome), cleft lip/palate, deafness and flat nasal bridge camplodactyly and hyperlaxity in the human (Trarbach et al., 2010). |
5. Implicated in
Note | |
Entity | Breast and prostate cancers |
Disease | In humans FGF8 has been shown to be expressed in benign breast and prostate lesions and in breast and prostate cancer (Tanaka et al., 1998; Leung et al., 1996; Dorkin et al., 1999). Furthermore, it has been detected in bone metastases of prostate cancer (Valta et al., 2008). The expression of FGF8 has been shown to be increased in breast cancer when compared to non-malignant breast tissue (Marsh et al., 1999). FGF8 expression is correlated with the expression of androgen receptor in both breast and prostate cancer (Tanaka et al., 2002; Wang et al., 1999). |
Prognosis | In prostate cancer the expression of FGF8 correlates with the poor prognosis (Dorkin et al., 1999). FGF8b is the primary isoform detected in breast cancer (Marsh et al., 1999) but in prostate cancer in addition to FGF8b, also FGF8a and FGF8e have been detected (Valve et al., 2001). Interestingly, both FGF8 isoforms a and e are expressed more commonly in prostate cancer than in benign prostate samples used as controls (Valve et al., 2001). Surprisingly, FGF8b, despite of being the most transforming isoform (Ghosh et al., 1996) is expressed in a similar manner in both benign and malignant prostate samples (Valve et al., 2001). The clinical data and experimental evidence strongly suggest that FGF8 has a role in the promotion of growth and progression of hormonal cancers. FGF8 has been shown to function as a potent autocrine growth factor in the stimulation of proliferation of breast and prostate cancer cells. In addition, its paracrine effects in terms of induction of angiogenesis and osteoblastic differentiation may contribute to tumor progression. |
Oncogenesis | When transfected to NIH-3T3 cells FGF8 induces anchorage independent growth of the cells and tumorigenesis in nude mice (Kouhara et al., 1994). MMTV-Fgf8 transgenic mice develop mammary and salivary gland neoplasia and ovarian stromal hyperplasia (Daphna-Iken et al., 1998). Targeted expression of FGF8 in transgenic mouse prostate has been shown to result in prostatic intraepithelial neoplasia, stromal hyperplasia and increased inflammation (Song et al., 2002; Elo et al., 2010). Several breast and prostate cancer cell lines transfected with FGF8 have been shown to exhibit increased growth properties. Also morphology and motility of the cells are reportedly altered in response to FGF8 overexpression (Mattila et al., 2001; Ruohola et al., 2001) indicating that FGF8 may affect cytoskeletal and adhesion molecule expression of cancer cells. Similar to FGF2, FGF8 has been shown to have angiogenic potential (Mattila et al., 2001). Increased FGF8 expression is associated with rich vasculature of fast growing tumors (Valta et al., 2008; Valta et al., 2009; Tuomela et al., 2010). As FGF8 has a central role in hormonal cancers which preferentially metastasize to bone, recent studies have focused on the question whether FGF8 has a role in bone metastasis. The first results show that FGF8 is involved in bone metastasis of prostate cancer (Valta et al., 2006; Valta et al., 2008). |
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7. Citation
This paper should be referenced as such : |
Mattila, M ; Hè_rkönen, P |
FGF8 (fibroblast growth factor 8 (androgen-induced)) |
Atlas Genet Cytogenet Oncol Haematol. 2011;15(10):811-815. |
Free journal version : [ pdf ] [ DOI ] |
On line version : http://atlasgeneticsoncology.usal.es/classic/Genes/FGF8ID40566ch10q24.html |
Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ] |
Soft Tissues: Myxoinflammatory fibroblastic sarcoma with t(1;10)(p22;q24) FGF8/
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8. External links
REVIEW articles | automatic search in PubMed |
Last year publications | automatic search in PubMed |
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