Expression of FGF8, FGF18, and FGFR4 in Gastroesophageal Adenocarcinomas

Jomrich, Gerd; Hudec, Xenia; Harpain, Felix; Winkler, Daniel; Timelthaler, Gerald; Mohr, Thomas; Marian, Brigitte; Schoppmann, Sebastian F.

doi:10.3390/cells8091092

Cited by 16 publications

(17 citation statements)

References 47 publications

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“…2e), FIRΔexon2 possibly cooperates with BRG1 in neural development through alternative splicing of FGF8 pre-mRNA processing 12 . FGF8 has been reported as a prognostic factor in adenocarcinoma of esophago-gasric junction 42 and contributes to radiation resistance in rectal cancer 43 . Furthermore, FIRΔexon2 was detected in human gastric cancers but not in mice tumor cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer

et al. 2020

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Brahma-related gene 1 (BRG1), an ATPase subunit of the SWItch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex controls multipotent neural crest formation by regulating epithelial-mesenchymal transition (EMT)-related genes with adenosine triphosphate-dependent chromodomain-helicase DNA-binding protein 7 (CHD7). The expression of BRG1 engages in pre-mRNA splicing through interacting RNPs in cancers; however, the detailed molecular pathology of how BRG1and CHD7 relate to cancer development remains largely unveiled. This study demonstrated novel post-transcriptional regulation of BRG1 in EMT and relationship with FIRΔexon2, which is a splicing variant of the far-upstream element-binding protein (FUBP) 1-interacting repressor (FIR) lacking exon 2, which fails to repress c-myc transcription in cancers. Previously, we have reported that FIR complete knockout mice (FIR −/− ) was embryonic lethal before E9.5, suggesting FIR is crucial for development. FIRΔexon2 acetylated H3K27 on promoter of BRG1 by CHIP-sequence and suppressed BRG1 expression post-transcriptionally; herein BRG1 suppressed Snai1 that is a transcriptional suppressor of E-cadherin that prevents cancer invasion and metastasis. Ribosomal proteins, hnRNPs, splicing-related factors, poly (A) binding proteins, mRNA-binding proteins, tRNA, DEAD box, and WD-repeat proteins were identified as co-immunoprecipitated proteins with FIR and FIRΔexon2 by redoing exhaustive mass spectrometry analysis. Furthermore, the effect of FIRΔexon2 on FGF8 mRNA splicing was examined as an indicator of neural development due to impaired CHD7 revealed in CHARGE syndrome. Expectedly, siRNA of FIRΔexon2 altered FGF8 pre-mRNA splicing, indicated close molecular interaction among FIRΔexon2, BRG1 and CHD7. FIRΔexon2 mRNA was elevated in human gastric cancers but not in non-invasive gastric tumors in FIR +/ mice (K19-Wnt1/C2mE x FIR +/− ). The levels of FIR family (FIR, FIRΔexon2 and PUF60), BRG1, Snai1, FBW7, E-cadherin, c-Myc, cyclin-E, and SAP155 increased in the gastric tumors in FIR +/− mice compared to those expressed in wild-type mice. FIR family, Snai1, cyclin-E, BRG1, and c-Myc showed trends toward higher expression in larger tumors than in smaller tumors in Gan-mice (K19-Wnt1/C2mE). The expressions of BRG1 and Snai1 were positively correlated in the gastric tumors of the Gan-mice. Finally, BRG1 is a candidate substrate of F-box and WD-repeat domain-containing 7 (FBW7) revealed by three-dimensional crystal structure analysis that the U2AF-homology motif (UHM) of FIRΔexon2 interacted with tryptophan-425 and asparate-399 (WD)-like motif in the degron pocket of FBW7 as a UHM-ligand motif. Together, FIRΔexon2 engages in multi-step post-transcriptional regulation of BRG1, affecting EMT through the BRG1/Snai1/E-cadherin pathway and promoting tumor proliferation and invasion of gastric cancers.

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Section: Discussionmentioning

confidence: 99%

Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer

et al. 2020

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“…Immunohistochemistry (IHC) was performed as reported previously [36]. In brief, paraffin-embedded specimens fixed in 4% buffered formalin were used with 3-µm thick histological sections.…”

Section: Methodsmentioning

confidence: 99%

“…Stained sections were scanned using 3DHISTECH Ltd. (Budapest, Hungary) Pannoramic MIDI slides canner and analyzed and scored using Pannoramic Viewer 1.15.4 Software. Antibodies used in this study were optimized for PDAC on colorectal cancer and esophageal adenocarcinoma tissue with known expression from previously published studies [36][37][38].…”

Section: Methodsmentioning

confidence: 99%

“…The prognostic role of the fibroblast growth factors (FGF) 8 and 18, both members of the FGF subfamily 8, were investigated in a number of malignancies [30][31][32][33][34][35]. Whereas the majority of studies describe diminished patient prognosis in cancers overexpressing FGF8 and FGF18, a protective effect of FGF18 has been found for gastroesophageal adenocarcinomas [36]. Furthermore, there are increasing data on the use of FGF ligand traps and fibroblast growth factor receptor (FGFR) inhibitors to overcome chemoresistance in various cancers, including pancreatic tumors [37][38][39].…”

Section: Original Articlementioning

confidence: 99%

“…Due to these characteristics, overexpression of FGFs can promote carcinogenesis and distant metastasis, and therefore have a fundamental role in cancer [21]. In a number of malignancies, including gastric cancer, gastroesophageal adenocarcinoma, and PDAC, the prognostic role of aberrant FGF expression was investigated [30,35,36,38,39]. However, to date, only few data on the expression of FGF8 and FGF18 in PDAC are available [23].…”

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Fibroblast growth factor 8 overexpression is predictive of poor prognosis in pancreatic ductal adenocarcinoma

et al. 2020

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Summary Background Despite distinctive advances in the field of pancreatic cancer therapy over the past few years, patient survival remains poor. Fibroblast growth factors 8 (FGF8) and 18 (FGF18) both play a role in modulating the activity of malignant cells and have been identified as promising biomarkers in a number of cancers. However, no data exist on the expression of FGF8 and FGF18 in pancreatic ductal adenocarcinoma (PDAC). Methods Protein expression levels of FGF8 and FGF18 in postoperative specimens of neoadjuvantly treated and primarily resected patients were investigated using immunohistochemistry. Immunostaining scores were calculated as the products of the staining intensity and the staining rate. Scores exceeding the median score were considered as high expression. Results Specimens from 78 patients with PDAC were available and met the eligibility criteria for analysis of protein expression using immunohistochemistry. 15 (19.2%) patients had received neoadjuvant chemotherapy. High protein levels of FGF8 and FGF18 were detected in 40 (51.8%) and 33 (42.3%) patients, respectively. Kaplan–Meier analysis demonstrated significantly shorter overall survival in patients with high expression of FGF8 (p = 0.04). Multivariable Cox proportional hazard regression models revealed that high expression of FGF8 (Hazard ratio [HR] 0.53, 95% Confidence interval [CI] 0.32–0.89, p = 0.016) was an independent prognostic factor for diminished overall survival in patients with PDAC. By contrast, no statistical significance was found for FGF18 overexpression. In addition, the FGF8 protein level correlated with the factor resection margin (p = 0.042). Conclusion FGF8 is a promising target for new anticancer therapies using FGF inhibitors in pancreatic ductal adenocarcinomas.

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