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Bile Acids in the Pathogenesis of Necrotizing Enterocolitis
Published in David J. Hackam, Necrotizing Enterocolitis, 2021
Most BA reclamation occurs in the distal ileum via the apical sodium-dependent bile acid transporter (ASBT) (10). The intestinal bile acid–binding protein (IBABP, aka FABP6) is thought to shuttle internalized BAs to the basolateral surface of enterocytes (11, 12), where the heteromeric organic solute transporter (OSTα-OSTβ) effluxes BAs into portal circulation (13). On hepatocytes, the sodium-dependent taurocholate-transporting polypeptide (NTCP) and members of the organic anion-transporting polypeptide (OATP) family mediate the completion of enterohepatic circulation. The farnesoid X receptor (FXR) is a nuclear receptor for which BAs are endogenous ligands (14, 15). When BAs bind to FXR in the liver, a cascade of events occurs, eventually leading to suppression of CYP7A1 and NTCP with up-regulation of BSEP. In the intestine, activation of FXR by BAs down-regulates ASBT and up-regulates IBABP and OSTα-OSTβ (16, 17). Binding of BAs to FXR also activates fibroblast growth factor 19 (FGF19) in humans and FGF15 in mice. FGF15/19, an intestinal hormone, is secreted into portal circulation and in the liver and suppresses CYP7A1 and BA synthesis after binding to FGF receptor 4 (FGFR4) complexed with β-Klotho (18). This highly regulated process provides an effective mechanism for recycling BAs and preventing toxic accumulation in enterocytes and hepatocytes (19, 20).
Genetic and Biological Alterations in Cancer
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
Peptide growth factors play an important role in carcinogenesis and are currently the best exploited in terms of new drug development. Ligands bind to their cognate receptors at the cell membrane and initiate a cascade of downstream signalling that is in general promitogenic and antiapoptotic. The key growth factors implicated in cancer include fibroblast growth factors (FGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), and transforming growth factor (TGF). In cancer cells, alterations at every level of growth factor regulation have been found. In prostate cancer both growth factor ligands and receptors have been shown to be upregulated in carcinogenesis and tumor progression (39–41). In the FGF axis for instance, ligands including FGF1, 2, 8, and 17 have been shown to be increased in high-grade and high-stage disease (42–44). FGF10 has been recently implicated as an important stromal-epithelial initiator of prostate tumor development (45). FGF receptor (FGFR)1 is known to be overexpressed as an early event in clinical prostate cancer, and induced expression is causative in the development and progression of tumor in a mouse model (46, 47). FGFR4 in contrast is preferentially overexpressed in more advanced tumors.
Genetics of gastric cancer
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
HST-1 was originally identified as a transforming gene from studies that involved transfecting NIH-3T3 cells with DNA samples from gastric carcinomas and adjacent non-neoplastic gastric mucosa (Sakamoto et al., 1986). It is homologous to fibroblast growth factor receptor 4 (FGFR4) and is located on chromosome 11q13 (Sakamoto et al., 1986). FGFR4 has been shown to be co-amplified with INT-2 in a variety of tumor types including urinary bladder carcinomas, melanomas, esophageal carcinomas as well as gastric cancers (Yoshida et al., 1988). The INT-2 gene, which was subsequently shown to be the FGF3 gene, has been implicated in mouse mammary carcinogenesis, is activated by viral insertion, and is located adjacent to FGFR4 on chromosome 11. FGFR4 amplification in gastric cancer (2%, n = 1/43) has been shown in one study (Yoshida et al., 1988). However, Tsuda et al. found no amplification of either gene in 42 gastric carcinomas but co-amplification of both genes in 50% of esophageal carcinomas (Tsuda et al., 1989). Finally, amplification of FGFR4 does not correlate with overexpression of the FGFR4 gene product. Thus, the role FGFR4/FGR3 plays in gastric cancer formation is uncertain.
Genetic variants of FGFR family associated with height, hypertension, and osteoporosis
Published in Annals of Human Biology, 2023
Hye-Won Cho, Hyun-Seok Jin, Yong-Bin Eom
Among four genetic variants (rs199545667, rs1530587, rs10212860, and rs351855) which were predicted motif changes, rs1530587 and rs10212860 in the FGFR3 gene had a RegulomeDB score of 2b and rs351855 in the FGFR4 gene had 15 expression quantitative trait loci (eQTL) hits (Table 3). Expression of FGFR2, FGFR3, and FGFR4, which showed association with two of the three phenotypes in bone-related cells were confirmed and present roles in bone growth (Supplementary Figure 1). Also, the GTEx database analysis produced single-tissue QTLs of genetic variants in the FGFR3 gene (Figure 3). Three genetic signals in FGFR3 (rs1530587, rs116721553, and rs10212860) were identified as significant signals for the FGFR3 gene in the pituitary and hypothalamus, at p<1 × 10−12 (Figure 3).
6-Amino-2,4,5-trimethylpyridin-3-ol and 2-amino-4,6-dimethylpyrimidin-5-ol derivatives as selective fibroblast growth factor receptor 4 inhibitors: design, synthesis, molecular docking, and anti-hepatocellular carcinoma efficacy evaluation
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Chhabi Lal Chaudhary, Dongchul Lim, Prakash Chaudhary, Diwakar Guragain, Bhuwan Prasad Awasthi, Hee Dong Park, Jung-Ae Kim, Byeong-Seon Jeong
Fibroblast growth factor receptor 4 (FGFR4), one of the families of fibroblast growth factor receptors, is a tyrosine kinase receptor with a distinct 802 amino acid sequence. Normally, FGFR4 expression level is high during foetal development and drastically reduced thereafter5. Most of FGF family members, except FGF11 subfamily, are ligands of FGFR46. FGF19, which is produced from the ileum as a postprandial hormone, has a more specific selective affinity to FGFR4 than the other FGF ligands. In contrast to the normal production and action of FGF19 as an endocrine hormone, FGF19 is overexpressed and co-expressed with FGFR4 in various cancers of liver, breast, lung, bladder, head, and neck7–10, indicating FGF19 as a driver oncogene. Similarly, amplification of FGFR4 gene is the predominant type and accounts for 78% of all FGFR4 gene alterations in various cancers11–14. In addition, a significant correlation between overexpression of FGFR4 in tumour tissues and patients’ poor survival rate indicates FGFR4 is also acting as an oncogene15,16.
A short report on NGM282/aldafermin for the treatment of nonalcoholic steatohepatitis (NASH)
Published in Expert Opinion on Therapeutic Targets, 2021
Stuart K Roberts, Ammar Majeed
Several members of the fibroblast growth factor (FGF) family are involved in the regulation of cellular response to injury, specifically cellular proliferation, migration, and differentiation [41]. Notably, some FGFs are also involved in carcinogenesis of different types of tumors. Transgenic mice overexpressing FGF8 develop breast tumors [42], while those overexpressing FGF10 form pulmonary adenomas [43]. Importantly, Nicholes et al. described that transgenic mice overexpressing human FGF19 in skeletal muscles developed foci of liver dysplasia and HCC by the age of 10–12 months [34]. This hepatocarcinogenic effect of FGF19 is thought to be mediated through FGFR4 signaling. Targeting FGFR4 by using antibodies or inactivation of FGFR4 in knock-out transgenic mice reduced or inhibits the growth of HCC in animal models [44,45].