Disease relevance of FGF7

• However, unlike the Apert syndrome Pro253Arg FGFR2c mutant, neither the Pfeiffer syndrome Pro250Arg FGFR1c mutant nor the Muenke syndrome Pro250Arg FGFR3c mutant bound appreciably to FGF7 or FGF10 [1].
• To better define the role of FGF2 and FGF7 in human prostate cancer in vivo, we have quantified these two growth factors in clinically localized human prostate cancers and uninvolved prostate by ELISA and Western blotting and determined their localization by immunohistochemistry [2].
• FGF7 and FGF2 are increased in benign prostatic hyperplasia and are associated with increased proliferation [3].
• These findings suggest that FGF7 plays a significant role in the development of ovarian cancer [4].
• Using an FGF7-specific antibody which does not react with the FGF7 heparan sulphate proteoglycan (HSPG)-binding site, we showed epithelial and myoepithelial immunohistochemical staining in normal breast sections, and epithelial staining in breast carcinomas [5].
• HKGF gene transfer to salivary glands prevented radiation-induced oral mucositis in mice [6].

High impact information on FGF7

• The function of keratinocyte growth factor (KGF) in normal and wounded skin was assessed by expression of a dominant-negative KGF receptor transgene in basal keratinocytes [7].
• The function of KGF in morphogenesis of epithelium and reepithelialization of wounds [7].
• We investigated the expression and distribution of keratinocyte growth factor (KGF) (FGF-7) and its receptor (KGFR) during reepithelialization of human skin [8].
• Suramin, which blocked KGF binding and stripped already bound KGF from its receptor, failed to unmask KGFRs in tissue sections from the intermediate phase of wound repair [8].
• As an indication of specificity, the inflammatory cells and fibroblasts within the wound were not influenced by KGF [9].

Chemical compound and disease context of FGF7

• In conclusion, KGF prolongs survival during LPS- and GalN-induced hepatic failure by temporarily protecting hepatocytes against apoptosis [10].
• In the present study, we focused on keratinocyte growth factor (KGF) and its receptor (KGFR) in the pathogenesis of breast cancer, as a growth factor mediating estrogen action, since significant roles of KGF were demonstrated in various steroid hormone-dependent tissues [11].
• CONCLUSION: These results suggest that KGF and SF may have an important role in cyclosporin-induced gingival overgrowth [12].
• In situ hybridization studies with digoxigenin-labeled oligonucleotides (anti-sense and sense controls) were employed to examine KGF and KGF receptor mRNA expression in prostate cancer [13].
• The in vitro findings are clinically relevant because KGF protected keratinocytes in organ-cultured human scalp hair follicles from the toxicity of the xenobiotic menadione [14].

Biological context of FGF7

• Among the FGFs, FGF7 and FGF10 have been implicated in the regulation of prostate development and prostate tissue homeostasis by signaling through the FGFR2 isoform [15].
• Using a panel of deletion mutants, FGF-BP binding was localized to the second EGF repeat of domain III, a region very close to the binding site for FGF7 [16].
• Thus, by mimicking the paracrine pathway (on proliferation, growth in soft agar and invasion) on the human prostatic epithelial cell line PNT1A positively checked for FGFR2/IIIb expression, FGF7 significantly enhanced cell proliferation at an optimal concentration of 7.5 x 10(-11) M, but no significant invasion or growth in soft agar were observed [17].
• Southern blot analysis showed multiple FGF7-like genes in the 9p11 region which were also duplicated to the 9q13 region on the aberrant chromosome 9 [4].
• DNA sequence analysis showed that the cosmid clones spanned the 57.7-kb sequence, which contained the FGF7 [keratinocyte growth factor (KGF)]-like gene including exons 2 and 3 [4].

Anatomical context of FGF7

• Both subtypes expressed FGF7 and equally low levels of FGFR2IIIc mRNA, whereas fibroblast growth factor receptor (FGFR) 1 predominated in DTS1 cells [18].
• This method allowed us to demonstrate that human embryonic pancreatic mesenchyme expresses FGF7 and FGF10 that act on epithelial cells to activate their proliferation [19].
• RESULTS: We found that different FGFs are expressed in the human embryonic pancreas, and we focused on FGF7 and FGF10 [19].
• FGF9 is a potent mitogen for both prostatic epithelial and stromal cells in culture and is a more potent mitogen for these cells than either FGF2 or FGF7, two other FGFs expressed in the human prostate [20].
• We also examined the effects of FGF7 on Matrigel-embedded organoids, containing both epithelial and myoepithelial cells, and showed FGF7 induced an increase in cellular proliferation [5].

Associations of FGF7 with chemical compounds

• FGF2-Heparin co-crystal complex-assisted design of mutants FGF1 and FGF7 with predictable heparin affinities [21].
• Finally, we showed that interleukin-1beta, but not oestradiol or other oestrogen receptor ligands, caused a dose-related FGF7 release [5].
• A model is proposed whereby androgen regulates TGF beta, influencing FGF2 and FGF7 expression, and in turn regulating growth of the prostatic stroma and epithelium [22].
• In the present study we examined the potential morphogenic activities of the growth factors FGF1, FGF2 and FGF7, and cellular processes underlying morphogenesis, in pancreatic cells from streptozotocin diabetic newborn rats [23].
• Cell proliferation analysis indicated that tamoxifen or ICI 182,780 reduced cell viability in a dose-dependent manner; however, KGF prevented this inhibition, which further demonstrated KGF triggered anti-apoptotic machinery through activating Bcl-2 and phospho-Akt expression [24].

Physical interactions of FGF7

• The protein core of the proteoglycan perlecan binds specifically to fibroblast growth factor-7 [25].
• K-sam generates several variant transcripts by alternative splicing, and the most abundant K-sam transcript in KATO-III cells was cloned as the K-sam-IIC3 cDNA, which has the KGF-binding motif and a short carboxyl terminus lacking a putative phospholipase C-gamma 1 association site, Tyr-769 [26].

Regulatory relationships of FGF7

• However, FGF10 is expressed at extremely low levels relative to FGF7, which has a similar biological activity [27].
• FGF-7 stimulation was significantly inhibited by PD-98059 and wortmannin suggesting mediation via MAP kinase and PI-3 kinase-dependent signaling pathways [28].
• Additional mRNA transcripts encoding FGF-5 and FGF-7 were expressed by RA, but not normal, synovial cells in culture [29].
• KGF stimulated the proliferation of cyst-lining epithelial cell in vitro by regulating the expression of cyclin D1 and P21(wafl) genes [30].
• We show that treatment with KGF (10 ng/ml) potently induces epithelial differentiation with concomitant suppression of alpha2beta1 integrin expression as well as the induction of androgen receptor expression [31].
• Our results demonstrate for the first time that KGF/FGF-7 induces NF-kappaB activation and that NF-kappaB plays an essential role in regulation of KGF/FGF-7-inducible gene expression and KGF/FGF-7-initiated cellular responses [32].

Other interactions of FGF7

• Keratinocyte growth factor (KGF) and epidermal growth factor (EGF), at concentrations of 50 ng/ml, activated CAT reporter gene transcription only in experiments in which the artificial promoter with two androgen-responsive elements was used [33].
• In contrast, the glioblastoma cell line, A-172, that expressed the bFGF receptor showed a mitogenic response to bFGF but not to KGF [34].
• Our results provide evidence that IGF-I, KGF, and EGF directly activate the AR in the absence of androgens, which means that the androgen-signaling chain may be activated by growth factors in an androgen-depleted environment [33].
• In this report we examined the specific binding of FGF7 to various domains and subdomains of perlecan protein core [25].
• The isoforms which bind KGF (keratinocyte growth factor or FGF-7) are called KGF-R or FGFR2b [35].
• Short hairpin-KGFR transfection in MIA PaCa-2 cells reduced the stimulatory effect of exogenous KGF on VEGF-A expression [36].

Analytical, diagnostic and therapeutic context of FGF7

• To investigate the cell types expressing FGF7 and FGF10, we separated epithelial from mesenchymal cells using immunomagnetic beads linked to E-cadherin antibodies and performed real-time PCR [19].
• A neutralizing monoclonal antibody to FGF7 reversed FGF7-dependent phosphate transport inhibition and inhibitory activity in conditioned medium from tumor cell cultures [37].
• Immunoassay revealed abundant FGF7 in inhibitory conditioned medium and minimal amounts in nonconditioned medium or conditioned medium with no phosphate transport inhibitory activity [37].
• Consistent with these in vitro effects, quantitative analysis of cellular proliferation by Ki67 immunohistochemistry revealed a strong correlation of epithelial proliferation with FGF7 content in BPH tissue, consistent with a key role for this growth factor in driving the abnormal epithelial proliferation in BPH [3].
• Loss of resident epithelial cell FGFR2IIIb that responds to stromal FGF7 and FGF10 accompanies malignant progression of both model animal and human prostate tumors [38].

References