Role Of Fibroblast Growth Factor Receptor 2 Research Articles

Nuclear FGFR2 negatively regulates hypoxia-induced cell invasion in prostate cancer by interacting with HIF-1 and HIF-2

The fibroblast growth factor receptor 2 (FGFR2) is a membrane receptor that promotes cell proliferation and differentiation. FGFR2 is also present in the nucleus, which raises a question on a new role of FGFR2 in regulating gene expression. Hypoxia-inducible factors 1 and 2 (HIF-1 and HIF-2) are nuclear proteins that transactivate many genes essential for cancer survival and metastasis under hypoxic conditions. Here, we investigated if nuclear FGFR2 modulates the HIF-driven hypoxic response. Using the TCGA database, we found that FGFR2 downregulation is associated with poor prognosis in prostate cancer. A gene-set enrichment analysis showed that metastasis- and hypoxia-related genes are associated with a low expression of FGFR2 in prostate cancer. Thus, we tested the possibility that FGFR2 negatively regulates the hypoxia-triggered metastasis of prostate cancer. FGFR2 controls migration and invasion of prostate cancer cells under hypoxia by inhibiting the HIF-driven gene expression. FGFR2 and HIF proteins co-localize and associate in the nucleus under hypoxia. FGFR2 interacts with the transactivation domain of HIF-1α and blocks the recruitment of coactivator p300, resulting in repression of HIF target genes. Based on these results, we propose a novel function of FGFR2 as a metastasis suppressor by controlling HIF-mediated hypoxic responses.

Transcriptome analysis of endometrial stroma-like cells derived from human induced pluripotent stem cells identifies a potential endometrial stem cell marker

The endometrium is known to undergo regeneration with each menstrual cycle, and stem cells are the source of this regeneration. Our group recently established a 14-day protocol, which enables in vitro differentiation of human induced pluripotent stem cells (hiPSC) into progesterone responsive endometrial stroma-like cells. The objective of this study is to identify a novel cell surface marker for isolation and characterization of endometrial tissue stem cells based on our endometrial differentiation model. Prospective experimental design. Transcriptome analysis was performed on RNA-Sequencing (RNA-Seq) data (unpublished data) to find differentially expressed cell surface markers during hiPSC differentiation. The results of RNA-seq at various differentiation points (day 0: hiPSCs, day 4: intermediate mesoderm, day 6: coelomic epithelium, day 8: mullerian duct, day 14: endometrial stroma) were confirmed by RT-qPCR. Endometrial tissue obtained from hysterectomies was enzymatically digested and cell suspension was filtered through a 20 micron-sieve for isolating stromal portion of the endometrium. Fibroblast Growth Factor Receptor 2 (FGFR2) (+) cells were sorted using magnetic-activated cell sorting from freshly isolated stromal cells. mRNA expression profile was investigated by RT-qPCR. Paraffin-embedded whole endometrial tissue was stained with FGFR2 antibody for immunohistochemistry. Analysis of RT-qPCR confirmed transcriptome data over the course of differentiation revealed that mRNA levels of FGFR2 peaked at day 8 and robustly decreased at day 14. This expression pattern was similar to putative endometrial mesenchymal stem cell marker SUSD2, with maximal expression at mullerian duct (MD) stage and a robust decline on day 14. The similarities in the mRNA expression profile, as well as the role of FGFR2 in embryonic development and stem cell maintenance, led us to hypothesize that FGFR2 could be a novel stem cell marker for the endometrial stroma. Immunohistochemistry staining showed that FGFR2 protein is located in the perivascular region of the endometrial stroma and is more frequently expressed in the basalis portion. FGFR2(+) cells compose 2.35% (1.79-2.82%) of the stroma enhanced portion of the endometrium. FGFR2(+) cells have higher expression of putative endometrial stem cell markers ABCG2 and SUSD2, MD marker ISL1, pluripotency marker KLF4, and lower expression of differentiated endometrial markers ESR1 and PGR. FGFR2(+) cells have a stem cell-like phenotype with decreased expression of mature tissue markers and increased expression of early differentiation markers. Isolation of FGFR2(+) cells can help characterization of endometrial stem cells and investigation of their role in gynecologic diseases such as endometriosis.

Abstract 2156: FGFR2 regulates Mre11 expression and double-strand break repair via the MEK-ERK-POU1F1 pathway in breast tumorigenesis

Abstract Purpose: The association between breast cancer risk and genetic variants of fibroblast growth factor receptor 2 (FGFR2) has been identified and repeatedly confirmed; however, the mechanism underlying FGFR2 in breast tumorigenesis remains obscure. Given that breast tumorigenesis is particularly related to DNA double-strand-break-repair (DSBR), we examined the hypothesis that FGFR2 is involved in DSBR. Experimental design: This study started with the demonstration that FGFR2 impaired DSBR. Subsequent screening of the expression of genes functionally related to DSBR was performed and possible signaling pathways downstream of FGFR2 were examined. Data from independent breast cancer patient cohorts was used to confirm that difference in progression of patients can be explained by the findings identified in cell model. Results: Expression of Mre11, a vital exonuclease in DSBR, is downregulated by FGFR2, which is further linked to decreased DSBR. Analysis of the Mre11 promoter revealed that POU1F1 mediates FGFR2-induced Mre11 downregulation. Furthermore, ERK, downstream of FGFR2, directly interacts with and phosphorylates POU1F1, increasing POU1F1 binding capacity to the Mre11 promoter and repressing Mre11 expression, which consequently affects DSBR and sensitizes breast cancer cells to chemotherapeutic treatments. The importance of the FGFR2-Mre11-DSBR link in cancer progression is suggested by the finding that genotypes of FGFR2 and Mre11 are associated with survival of breast cancer patients and that FGFR2 expression correlates with cancer prognosis specifically in patients receiving chemotherapy. Conclusion: This study yields important insight into the role of FGFR2 in breast tumorigenesis and may facilitate development of a useful therapeutic approach for breast cancer. With the move toward personalized therapy, which has gradually become a clinical reality, the findings of the present study suggest that FGFR2 expression may be a potential biomarker for selecting a suitable subgroup of breast cancer patients to receive chemotherapy or to determine the optimal chemotherapeutic dose. Citation Format: Yuan-Ling Huang, Wen-Cheng Chou, Chia-Ni Hsiung, Ling-Yueh Hu, Hou-Wei Chu, Chen-Yang Shen. FGFR2 regulates Mre11 expression and double-strand break repair via the MEK-ERK-POU1F1 pathway in breast tumorigenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2156. doi:10.1158/1538-7445.AM2015-2156

FGFR2 regulates Mre11 expression and double-strand break repair via the MEK-ERK-POU1F1 pathway in breast tumorigenesis.

The association between breast cancer risk and genetic variants of fibroblast growth factor receptor 2 (FGFR2) has been identified and repeatedly confirmed; however, the mechanism underlying FGFR2 in breast tumorigenesis remains obscure. Given that breast tumorigenesis is particularly related to DNA double-strand-break-repair (DSBR), we examined the hypothesis that FGFR2 is involved in DSBR. Our results show that expression of Mre11, a vital exonuclease in DSBR, is downregulated by FGFR2, which is further linked to decreased DSBR. Analysis of the Mre11 promoter revealed that POU1F1 mediates FGFR2-induced Mre11 downregulation. Furthermore, ERK, downstream of FGFR2, directly interacts with and phosphorylates POU1F1, increasing POU1F1 binding capacity to the Mre11 promoter and repressing Mre11 expression, which consequently affects DSBR and sensitizes breast cancer cells to chemotherapeutic treatments. The importance of the FGFR2-Mre11-DSBR link in cancer progression is suggested by the finding that genotypes of FGFR2 and Mre11 are associated with survival of breast cancer patients and that FGFR2 expression correlates with cancer prognosis specifically in patients receiving chemotherapy. This study yields important insight into the role of FGFR2 in breast tumorigenesis and may facilitate development of a useful therapeutic approach for breast cancer.

Fibroblast growth factor receptor 2 (FGFR2) is required for corneal epithelial cell proliferation and differentiation during embryonic development.

Fibroblast growth factors (FGFs) play important roles in many aspects of embryonic development. During eye development, the lens and corneal epithelium are derived from the same surface ectodermal tissue. FGF receptor (FGFR)-signaling is essential for lens cell differentiation and survival, but its role in corneal development has not been fully investigated. In this study, we examined the corneal defects in Fgfr2 conditional knockout mice in which Cre expression is activated at lens induction stage by Pax6 P0 promoter. The cornea in LeCre, Fgfr2loxP/loxP mice (referred as Fgfr2CKO) was analyzed to assess changes in cell proliferation, differentiation and survival. We found that Fgfr2CKO cornea was much thinner in epithelial and stromal layer when compared to WT cornea. At embryonic day 12.5–13.5 (E12.5–13.5) shortly after the lens vesicle detaches from the overlying surface ectoderm, cell proliferation (judged by labeling indices of Ki-67, BrdU and phospho-histone H3) was significantly reduced in corneal epithelium in Fgfr2CKO mice. At later stage, cell differentiation markers for corneal epithelium and underlying stromal mesenchyme, keratin-12 and keratocan respectively, were not expressed in Fgfr2CKO cornea. Furthermore, Pax6, a transcription factor essential for eye development, was not present in the Fgfr2CKO mutant corneal epithelial at E16.5 but was expressed normally at E12.5, suggesting that FGFR2-signaling is required for maintaining Pax6 expression in this tissue. Interestingly, the role of FGFR2 in corneal epithelial development is independent of ERK1/2-signaling. In contrast to the lens, FGFR2 is not required for cell survival in cornea. This study demonstrates for the first time that FGFR2 plays an essential role in controlling cell proliferation and differentiation, and maintaining Pax6 levels in corneal epithelium via ERK-independent pathways during embryonic development.

RNA interference screening identifies a novel role for autocrine fibroblast growth factor signaling in neuroblastoma chemoresistance

Chemotherapeutic drug resistance is one of the major causes for treatment failure in high-risk neuroblastoma (NB), the most common extra cranial solid tumor in children. Poor prognosis is typically associated with MYCN amplification. Here, we utilized a loss-of-function kinome-wide RNA interference screen to identify genes that cause cisplatin sensitization. We identified fibroblast growth factor receptor 2 (FGFR2) as an important determinant of cisplatin resistance. Pharmacological inhibition of FGFR2 confirmed the importance of this kinase in NB chemoresistance. Silencing of FGFR2 sensitized NB cells to cisplatin-induced apoptosis, which was regulated by the downregulation of the anti-apoptotic proteins BCL2 and BCLXL. Mechanistically, FGFR2 was shown to activate protein kinase C-δ to induce BCL2 expression. FGFR2, as well as the ligand fibroblast growth factor-2, were consistently expressed in primary NB and NB cell lines, indicating the presence of an autocrine loop. Expression analysis revealed that FGFR2 correlates with MYCN amplification and with advanced stage disease, demonstrating the clinical relevance of FGFR2 in NB. These findings suggest a novel role for FGFR2 in chemoresistance and provide a rational to combine pharmacological inhibitors against FGFR2 with chemotherapeutic agents for the treatment of NB.

Abstract 4586: Essential role of fibroblast growth factor receptor 2 (FGFR2) in tumorigenesis of human cancers with activated FGFR2 signaling demonstrated by functional blocking antibodies

Abstract Aberrant activation of fibroblast growth factor receptor 2 (FGFR2) signaling, through overexpression of FGFR2 and/or its ligands, mutations, and receptor amplification have been found in a variety of human tumors. We generated monoclonal antibodies against the extracellular ligand binding domain of FGFR2 to address the role of FGFR2 in tumorigenesis and to explore the potential of FGFR2 as a novel therapeutic target. We identified a broad panel of human cancer cell lines with dysregulated FGFR2 signaling and examined the sensitivity of these human cell lines to monoclonal antibodies specifically targeting FGFR2. These FGFR2 antibodies potently suppressed ligand-induced phosphorylation of FGFR2 and downstream signaling, as well as cell proliferation in vitro. The administration of FGFR2 monoclonal antibodies in mice significantly inhibited the growth of human cancer xenografts harboring activated FGFR2 signaling. Our findings support that dysregulated FGFR2 signaling is one of the critical oncogenic pathways involved in the initiation and/or maintenance of tumors. Cancer patients with aberrantly activated/amplified FGFR2 signaling could potentially benefit from therapeutic intervention with FGFR2-targeting antibodies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4586. doi:10.1158/1538-7445.AM2011-4586