FGFRL1 Promotes Ovarian Cancer Progression by Crosstalk with Hedgehog Signaling

Fibroblast growth factor receptor-like-1 (FGFRL1) has been identified as the fifth fibroblast growth factor receptor. So far, little is known about its biological functions, particularly in cancer development. Here, for the first time, we demonstrated the roles of FGFRL1 in ovarian carcinoma (OC). An array and existing databases were used to investigate the expression profile of FGFRL1 and the relationship between FGFRL1 expression and clinicopathological parameters. FGFRL1 was significantly upregulated in OC patients, and high FGFRL1 expression was correlated with poor prognosis. In vitro cell proliferation, apoptosis and migration assays, and in vivo subcutaneous xenograft tumor models were used to determine the role of FGFRL1. Loss of function of FGFRL1 significantly influenced cell proliferation, apoptosis, and migration of OC cells in vitro and tumor growth in vivo. Chromatin immunoprecipitation PCR analysis and microarray hybridization were performed to uncover the mechanism. FGFRL1 expression could be induced by hypoxia through hypoxia-inducible factor 1α, which directly binds to the promoter elements of FGFRL1. FGFRL1 promoted tumor progression by crosstalk with Hedgehog (Hh) signaling. Taken together, FGFRL1 is a potential predictor and plays an important role in tumor growth and Hh signaling which could serve as potential therapeutic targets for the treatment of OC.

[1]  Florian Steinberg,et al.  Receptor FGFRL1 acts as a tumor suppressor in nude mice when overexpressed in HEK 293 Tet-On cells , 2016, Oncology Letters.

[2]  Florian Steinberg,et al.  Receptor FGFRL1 does not promote cell proliferation but induces cell adhesion , 2016, International journal of molecular medicine.

[3]  M. Asada,et al.  Differential mRNA expression profiling in ovarian endometriotic tissue with versus without leuprolide acetate treatment , 2015, The journal of obstetrics and gynaecology research.

[4]  L. Zhuang,et al.  Cell-cell fusion induced by the Ig3 domain of receptor FGFRL1 in CHO cells. , 2015, Biochimica et biophysica acta.

[5]  J. Zuo,et al.  MiR‐210 Links Hypoxia With Cell Proliferation Regulation in Human Laryngocarcinoma Cancer , 2015, Journal of cellular biochemistry.

[6]  Christopher M. DeBoever,et al.  Systematic transcriptome analysis reveals tumor-specific isoforms for ovarian cancer diagnosis and therapy , 2015, Proceedings of the National Academy of Sciences.

[7]  M. Jarzab,et al.  Global Gene Expression Profiling in Three Tumor Cell Lines Subjected to Experimental Cycling and Chronic Hypoxia , 2014, PloS one.

[8]  B. Trueb,et al.  Role of FGFRL1 and other FGF signaling proteins in early kidney development , 2013, Cellular and Molecular Life Sciences.

[9]  Dawn M. Kilkenny,et al.  Fibroblast Growth Factor Receptor Like-1 (FGFRL1) Interacts with SHP-1 Phosphatase at Insulin Secretory Granules and Induces Beta-cell ERK1/2 Protein Activation* , 2013, The Journal of Biological Chemistry.

[10]  P. Yotnda,et al.  Induction and testing of hypoxia in cell culture. , 2011, Journal of visualized experiments : JoVE.

[11]  Michael J. Birrer,et al.  The Anterior Gradient Homolog 3 (AGR3) Gene Is Associated With Differentiation and Survival in Ovarian Cancer , 2011, The American journal of surgical pathology.

[12]  G. Tsujimoto,et al.  MicroRNA-210 Regulates Cancer Cell Proliferation through Targeting Fibroblast Growth Factor Receptor-like 1 (FGFRL1)* , 2010, The Journal of Biological Chemistry.

[13]  W. Wong,et al.  A gene signature predictive for outcome in advanced ovarian cancer identifies a survival factor: microfibril-associated glycoprotein 2. , 2009, Cancer cell.

[14]  S. Hayward,et al.  Hypoxia and the metabolic phenotype of prostate cancer cells. , 2009, Biochimica et biophysica acta.

[15]  P. Kuppusamy,et al.  Hypoxia induces chemoresistance in ovarian cancer cells by activation of signal transducer and activator of transcription 3 , 2009, International journal of cancer.

[16]  Ituro Inoue,et al.  Gene expression profiling of advanced‐stage serous ovarian cancers distinguishes novel subclasses and implicates ZEB2 in tumor progression and prognosis , 2009, Cancer science.

[17]  R. Jensen,et al.  Brain tumor hypoxia: tumorigenesis, angiogenesis, imaging, pseudoprogression, and as a therapeutic target , 2009, Journal of Neuro-Oncology.

[18]  S. Neuhauss,et al.  Fish possess multiple copies of fgfrl1, the gene for a novel FGF receptor. , 2005, Biochimica et biophysica acta.

[19]  L. Zhuang,et al.  Characterization of FGFRL1, a Novel Fibroblast Growth Factor (FGF) Receptor Preferentially Expressed in Skeletal Tissues* , 2003, Journal of Biological Chemistry.

[20]  J. Watson,et al.  Identification of a new fibroblast growth factor receptor, FGFR5. , 2001, Gene.

[21]  G. Koh,et al.  A novel fibroblast growth factor receptor-5 preferentially expressed in the pancreas(1). , 2001, Biochimica et biophysica acta.

[22]  B. Trueb,et al.  Characterization of a novel protein (FGFRL1) from human cartilage related to FGF receptors. , 2000, Genomics.

[23]  A. Harris,et al.  The expression and distribution of the hypoxia-inducible factors HIF-1α and HIF-2α in normal human tissues, cancers, and tumor-associated macrophages , 2000 .

[24]  D A Hilton,et al.  Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. , 1999, Cancer research.

[25]  A. Jemal,et al.  Cancer statistics, 2016 , 2016, CA: a cancer journal for clinicians.

[26]  Soken Tsuchiya.  [The role of microRNA-210 in esophageal squamous cell carcinoma]. , 2012, Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan.

[27]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.