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FGFR3 has tumor suppressor properties in cells with epithelial phenotype.

Lafitte M, Moranvillier I, Garcia S, Peuchant E, Iovanna J, Rousseau B, Dubus P, Guyonnet-Dupérat V, Belleannée G, Ramos J, Bedel A, de Verneuil H, Moreau-Gaudry F, Dabernat S - Mol. Cancer (2013)

Bottom Line: The receptor exerted dual effects: it suppressed tumor growth in pancreatic epithelial-like cells and had oncogenic properties in pancreatic mesenchymal-like cells.Both FGFR3 splice variants had similar effects and used the same intracellular signaling.TKIs against FGFR3 might result in adverse effects if used in the wrong cell context.

View Article: PubMed Central - HTML - PubMed

Affiliation: INSERM U1035, Université Bordeaux Segalen, 146 rue Léo Saignat, Bordeaux 33076, France.

ABSTRACT

Background: Due to frequent mutations in certain cancers, FGFR3 gene is considered as an oncogene. However, in some normal tissues, FGFR3 can limit cell growth and promote cell differentiation. Thus, FGFR3 action appears paradoxical.

Results: FGFR3 expression was forced in pancreatic cell lines. The receptor exerted dual effects: it suppressed tumor growth in pancreatic epithelial-like cells and had oncogenic properties in pancreatic mesenchymal-like cells. Distinct exclusive pathways were activated, STATs in epithelial-like cells and MAP Kinases in mesenchymal-like cells. Both FGFR3 splice variants had similar effects and used the same intracellular signaling. In human pancreatic carcinoma tissues, levels of FGFR3 dropped in tumors.

Conclusion: In tumors from epithelial origin, FGFR3 signal can limit tumor growth, explaining why the 4p16.3 locus bearing FGFR3 is frequently lost and why activating mutations of FGFR3 in benign or low grade tumors of epithelial origin are associated with good prognosis. The new hypothesis that FGFR3 can harbor both tumor suppressive and oncogenic properties is crucial in the context of targeted therapies involving specific tyrosine kinase inhibitors (TKIs). TKIs against FGFR3 might result in adverse effects if used in the wrong cell context.

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Phenotypic properties of PDAC cell lines. A) FGFR3 expression in the PDAC cell lines was determined by western-blot. FGFR3 expression was the highest in BxPC-3 cells and the lowest in Mia PaCa-2 cells. Membranes were reprobed for GAPDH to test equivalent loading. B) FGFR3 splice variants relative mRNA level were determined by RT-qPCR with specific primers and normalized with RPLP0 used as a mRNA expression internal reference. C) Epithelial E-cadherin and mesenchymal vimentin markers mRNA levels were determined by RT-qPCR. Capan-2 and BxPC-3 cells were epithelial, whereas the Mia PaCa-2 cell line was more mesenchymal. PANC-1 cells displayed an intermediate phenotype. D) Light microscope pictures of the four tested cell lines (original magnification ×40). PANC-1 presented an epithelial phenotype despite the strong expression of vimentin.
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Figure 2: Phenotypic properties of PDAC cell lines. A) FGFR3 expression in the PDAC cell lines was determined by western-blot. FGFR3 expression was the highest in BxPC-3 cells and the lowest in Mia PaCa-2 cells. Membranes were reprobed for GAPDH to test equivalent loading. B) FGFR3 splice variants relative mRNA level were determined by RT-qPCR with specific primers and normalized with RPLP0 used as a mRNA expression internal reference. C) Epithelial E-cadherin and mesenchymal vimentin markers mRNA levels were determined by RT-qPCR. Capan-2 and BxPC-3 cells were epithelial, whereas the Mia PaCa-2 cell line was more mesenchymal. PANC-1 cells displayed an intermediate phenotype. D) Light microscope pictures of the four tested cell lines (original magnification ×40). PANC-1 presented an epithelial phenotype despite the strong expression of vimentin.

Mentions: The different responses of the cells could be linked to various endogenous FGFR3 levels, before over-expression. Western-blots showed that BxPC-3 cells expressed the highest levels of the receptor, and the Mia PaCa-2 cells the lowest (Figure 2A). The two other cell lines displayed similar intermediate FGFR3 protein levels, but opposite behavior in response to FGFR3 forced expression. RT-qPCRs further showed that FGFR3-IIIb isoform was more abundant, except for the Mia PaCa-2 cells (Figure 2B). In addition total FGFR3 was detected by immunofluorescence in the cell lines, and we noticed that it had nuclear localization in PANC-1 and MiaPaCa-2 cells, but not in Capan-2 or BxPC-3 cells (Additional file 4: Figure S4). In Normal Human Keratinocytes (NHEK), signal was detected throughout the whole cells. Thus total FGFR3 levels or distinct FGFR3 splice variant relative abundance could not explain the opposite phenotypes.


FGFR3 has tumor suppressor properties in cells with epithelial phenotype.

Lafitte M, Moranvillier I, Garcia S, Peuchant E, Iovanna J, Rousseau B, Dubus P, Guyonnet-Dupérat V, Belleannée G, Ramos J, Bedel A, de Verneuil H, Moreau-Gaudry F, Dabernat S - Mol. Cancer (2013)

Phenotypic properties of PDAC cell lines. A) FGFR3 expression in the PDAC cell lines was determined by western-blot. FGFR3 expression was the highest in BxPC-3 cells and the lowest in Mia PaCa-2 cells. Membranes were reprobed for GAPDH to test equivalent loading. B) FGFR3 splice variants relative mRNA level were determined by RT-qPCR with specific primers and normalized with RPLP0 used as a mRNA expression internal reference. C) Epithelial E-cadherin and mesenchymal vimentin markers mRNA levels were determined by RT-qPCR. Capan-2 and BxPC-3 cells were epithelial, whereas the Mia PaCa-2 cell line was more mesenchymal. PANC-1 cells displayed an intermediate phenotype. D) Light microscope pictures of the four tested cell lines (original magnification ×40). PANC-1 presented an epithelial phenotype despite the strong expression of vimentin.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750311&req=5

Figure 2: Phenotypic properties of PDAC cell lines. A) FGFR3 expression in the PDAC cell lines was determined by western-blot. FGFR3 expression was the highest in BxPC-3 cells and the lowest in Mia PaCa-2 cells. Membranes were reprobed for GAPDH to test equivalent loading. B) FGFR3 splice variants relative mRNA level were determined by RT-qPCR with specific primers and normalized with RPLP0 used as a mRNA expression internal reference. C) Epithelial E-cadherin and mesenchymal vimentin markers mRNA levels were determined by RT-qPCR. Capan-2 and BxPC-3 cells were epithelial, whereas the Mia PaCa-2 cell line was more mesenchymal. PANC-1 cells displayed an intermediate phenotype. D) Light microscope pictures of the four tested cell lines (original magnification ×40). PANC-1 presented an epithelial phenotype despite the strong expression of vimentin.
Mentions: The different responses of the cells could be linked to various endogenous FGFR3 levels, before over-expression. Western-blots showed that BxPC-3 cells expressed the highest levels of the receptor, and the Mia PaCa-2 cells the lowest (Figure 2A). The two other cell lines displayed similar intermediate FGFR3 protein levels, but opposite behavior in response to FGFR3 forced expression. RT-qPCRs further showed that FGFR3-IIIb isoform was more abundant, except for the Mia PaCa-2 cells (Figure 2B). In addition total FGFR3 was detected by immunofluorescence in the cell lines, and we noticed that it had nuclear localization in PANC-1 and MiaPaCa-2 cells, but not in Capan-2 or BxPC-3 cells (Additional file 4: Figure S4). In Normal Human Keratinocytes (NHEK), signal was detected throughout the whole cells. Thus total FGFR3 levels or distinct FGFR3 splice variant relative abundance could not explain the opposite phenotypes.

Bottom Line: The receptor exerted dual effects: it suppressed tumor growth in pancreatic epithelial-like cells and had oncogenic properties in pancreatic mesenchymal-like cells.Both FGFR3 splice variants had similar effects and used the same intracellular signaling.TKIs against FGFR3 might result in adverse effects if used in the wrong cell context.

View Article: PubMed Central - HTML - PubMed

Affiliation: INSERM U1035, Université Bordeaux Segalen, 146 rue Léo Saignat, Bordeaux 33076, France.

ABSTRACT

Background: Due to frequent mutations in certain cancers, FGFR3 gene is considered as an oncogene. However, in some normal tissues, FGFR3 can limit cell growth and promote cell differentiation. Thus, FGFR3 action appears paradoxical.

Results: FGFR3 expression was forced in pancreatic cell lines. The receptor exerted dual effects: it suppressed tumor growth in pancreatic epithelial-like cells and had oncogenic properties in pancreatic mesenchymal-like cells. Distinct exclusive pathways were activated, STATs in epithelial-like cells and MAP Kinases in mesenchymal-like cells. Both FGFR3 splice variants had similar effects and used the same intracellular signaling. In human pancreatic carcinoma tissues, levels of FGFR3 dropped in tumors.

Conclusion: In tumors from epithelial origin, FGFR3 signal can limit tumor growth, explaining why the 4p16.3 locus bearing FGFR3 is frequently lost and why activating mutations of FGFR3 in benign or low grade tumors of epithelial origin are associated with good prognosis. The new hypothesis that FGFR3 can harbor both tumor suppressive and oncogenic properties is crucial in the context of targeted therapies involving specific tyrosine kinase inhibitors (TKIs). TKIs against FGFR3 might result in adverse effects if used in the wrong cell context.

Show MeSH
Related in: MedlinePlus