Abstract
Fibroblast growth factor 2 (FGF-2) is overexpressed in a subset of invasive bladder carcinomas and its overexpression correlates with poor prognosis. Analyses of publicly available databases addressing the molecular mechanisms that may be responsible for the poor prognosis of these tumors, revealed that FGF-2 expression correlates positively with the expression of epithelial to mesenchymal transition (EMT)-promoting transcription factors and with changes in gene expression that are characteristic of EMT. The same analyses also revealed that FGF-2 correlates negatively with the expression, mutation and copy number variations of FGFR-3, all of which are associated with noninvasive bladder carcinomas. Finally, they showed that FGF-2 expression correlates with the expression of FGFR-1, the expression of the IIIc variant of FGFR-2 and with the expression of Akt3. The latter observation is significant because our earlier studies had shown that Akt3 regulates FGFR-2 alternative splicing, shifting the balance toward the IIIc relative to the IIIb FGFR-2 splice variant. As the IIIc variant is recognized by FGF-2, while the IIIb variant is not, we conclude that Akt3 may facilitate the FGF-2 response. FGF-2 is known to promote the expression of KDM2B, which functions in concert with EZH2 to repress the EZH2-targeting microRNA miR-101, activating a switch, which stably upregulates EZH2. The cancer genome atlas (TCGA) data showing a correlation between KDM2B and EZH2 expression and Oncomine data, showing a correlation between KDM2B and tumor progression, strongly support the role of the FGF-2/KDM2B/miR-101/EZH2 pathway in bladder cancer. These observations combined, suggest a model according to which FGF-2 induces EMT, cell proliferation and cancer stem cell self-renewal by coupling the Akt3 and KDM2B-controlled pathways outlined above, in bladder carcinomas. Further analyses of publicly available databases, revealed that FGF-2-expressing bladder carcinomas carry fewer genetic alterations and they tend to express high levels of CTLA-4, PD-1 and PD-L1, which suggests immune blockade by checkpoint activation. EMT, enhanced proliferation and immune checkpoint activation combined, may be responsible for the poor prognosis of FGF-2-expressing bladder carcinomas.
Highlights
Bladder carcinomas are classified as either superficial or invasive, with the two types of tumors characterized by different sets of genomic alterations.[1,2] occasionally superficial tumors evolve to become invasive, the two types of bladder cancer represent distinct biological entities.[1,2] It is interesting that activating mutations in FGFR genes are common in the superficial form of bladder cancer, overexpression of fibroblast growth factor 2 (FGF-2) is often observed in invasive bladder cancer.[3,4,5]Our prior studies suggested at least two molecular mechanisms that may contribute to the invasiveness of FGF-2-expressing bladder carcinomas
Our studies have shown that Akt[3], and secondarily Akt[1], transduce signals that shift the alternative splicing of FGFR-2 toward the IIIc isoform, which is recognized by FGF-2
To address the mechanism by which FGF-2 promotes the aggressiveness of invasive bladder carcinomas, we examined the gene expression profiles of 407 muscle invasive bladder carcinomas in the The cancer genome atlas (TCGA) database and we observed that FGF-2 expression correlates with the expression of transcription factors that promote epithelial to mesenchymal transition (EMT) and stemness, as well as with the expression of mesenchymal markers, Signal Transduction and Targeted Therapy (2017) e16045
Summary
Bladder carcinomas are classified as either superficial or invasive, with the two types of tumors characterized by different sets of genomic alterations.[1,2] occasionally superficial tumors evolve to become invasive, the two types of bladder cancer represent distinct biological entities.[1,2] It is interesting that activating mutations in FGFR genes (primarily FGFR-3) are common in the superficial form of bladder cancer, overexpression of fibroblast growth factor 2 (FGF-2) is often observed in invasive bladder cancer.[3,4,5]. We addressed the distribution of genetic alterations in FGF-2 high and low context of the results of our earlier studies, these data suggest that groups focusing on (i) mutations per megabase and (ii) copy number the tumor phenotype may be due to the promotion of FGF-2 variations per tumor both obtained from cBioPortal. Resources revealed that high FGF-2 tumors are characterized by lower numbers of mutations per megabase and gene copy Correlations number variations, as well as by high expression of immune The TCGA data set was used to explore relationships between gene/exon checkpoint genes including CTLA-4, PDCD1 (PD-1) and CD274 (PD-L1).[13,14,15,16,17,18] These data suggest that tumors with high FGF-2expression tend to exhibit immune checkpoint activation, which may contribute, along with EMT and enhanced proliferaexpression, non-silent genetic mutations, and/or copy number alterations. Our observations raise the question whether FGF-2 expression identifies a subset of tumors with low numbers of genetic alterations that may respond to immune checkpoint inhibitors
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