Abstract
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.
Highlights
Ovarian carcinoma (OC) has the highest mortality rate among the malignancies of the female reproductive tract
The results showed that Fibroblast growth factor-like-1 (FGFRL1) expression was significantly upregulated in serous borderline ovarian tumors (SBOT), low-grade serous ovarian carcinomas (LGSOC), and high-grade serous ovarian carcinomas (HGSOC) in comparison with ovarian surface epithelia (OSE) using GSE27651 (n = 49, p = 0 0007, p < 0 0001, and p = 0 0013; Figure 1(a)) [18]
In OC cells, FGFRL1 expression could be induced by hypoxia via Hypoxia-Inducible Factor 1α (HIF1α)
Summary
Ovarian carcinoma (OC) has the highest mortality rate among the malignancies of the female reproductive tract. An insight into the understanding of the molecular mechanisms underlying the progression of OC and identifying new targets and strategies is pressing. Fibroblast growth factor-like-1 (FGFRL1) is a member of the fibroblast growth factor receptor (FGFR) family [2,3,4,5,6]. Fibroblast growth factors (FGF) and their receptors are known for regulating numerous cellular processes. Activated FGFRs have become a promising potential target in many cancers, including ovarian carcinoma. FGFRL1 was identified to enhance ERK1/2 signaling through association of SHP with the receptor’s intracellular SH2-binding motif in beta-cells in the pancreas
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