Basic fibroblast growth factor (bFGF), which plays an important role in tumour angiogenesis and progression, provides a potential target for cancer therapy. Here we screened a phage display heptapeptide library with bFGF and identified 11 specific bFGF-binding phage clones. Two of these clones had identical sequence and the corresponding peptide (referred to as P7) showed high homology to the immunoglobulin-like (Ig-like) domain III (D3) of high-affinity bFGF receptors, FGFR1 (IIIc) and FGFR2 (IIIc). The P7 peptide and its corresponding motif in D3 of FGFRs both carried negative charges and shared similar hydrophobic profiles. Functional analysis demonstrated that synthetic P7 peptides mediate strong inhibition of bFGF-induced cell proliferation and neovascularization. Our results demonstrate that the P7 peptide is a potent bFGF antagonist with strong antiangiogenetic activity, and might have therapeutic potential in cancer therapy.
Esophageal cancer is the eighth most common malignant tumor worldwide, of which esophageal squamous cell carcinoma (ESCC) is the dominant histological subtype. A drug shortage for ESCC therapy triggered us to explore the roles of fibroblast growth factor receptor 2 (FGFR2) and its upstream regulator miR-671-5p in ESCC progression. We compared the levels of FGFR2 and miR-671-5p between human ESCC tissues and their matched normal esophageal tissues and found an association between higher levels of FGFR2 and lower levels of miR-671-5p in ESCC tissues. High levels of FGFR2 resulted in the activation of the ERK and AKT pathways and a promotion of ESCC progression. High levels of miR-671-5p specifically reduced the expression of FGFR2 and suppressed ESCC progression in both in vitro and in vivo models. Therefore, suppressing FGFR2 and enhancing miR-671-5p expression may be the right approaches for ESCC therapy.
BackgroundBy using cDNA microarray analysis, we identified a G protein-coupled receptor, GPR39, that is significantly up-regulated in ESCC. The aim of this study is to investigate the role of GPR39 in human esophageal cancer development, and to examine the prevalence and clinical significance of GPR39 overexpression in ESCC.MethodsThe mRNA expression level of GPR39 was analyzed in 9 ESCC cell lines and 50 primary ESCC tumors using semi-quantitative RT-PCR. Immunohistochemistry was used to assess GPR39 protein expression in tissue arrays containing 300 primary ESCC cases. In vitro and in vivo studies were done to elucidate the tumorigenic role of GPR39 in ESCC cells.ResultsWe found that GPR39 was frequently overexpressed in primary ESCCs in both mRNA level (27/50, 54%) and protein level (121/207, 58.5%), which was significantly associated with the lymph node metastasis and advanced TNM stage (P < 0.01). Functional studies showed that GPR39 has a strong tumorigenic ability. Introduction of GPR39 gene into ESCC cell line KYSE30 could promote cell proliferation, increase foci formation, colony formation in soft agar, and tumor formation in nude mice. The mechanism by which amplified GPR39 induces tumorigenesis was associated with its role in promoting G1/S transition via up-regulation of cyclin D1 and CDK6. Further study found GPR39 could enhance cell motility and invasiveness by inducing EMT and remodeling cytoskeleton. Moreover, depletion of endogenous GPR39 by siRNA could effectively decrease the oncogenicity of ESCC cells.ConclusionsThe present study suggests that GPR39 plays an important tumorigenic role in the development and progression of ESCC.
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