MicroRNA-210 Regulates Cancer Cell Proliferation through Targeting Fibroblast Growth Factor Receptor-like 1 (FGFRL1)

Department of Nanobio Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi, Sakyo-ku, Kyoto 606-8501, Japan.
Journal of Biological Chemistry (Impact Factor: 4.57). 11/2010; 286(1):420-8. DOI: 10.1074/jbc.M110.170852
Source: PubMed


The importance of microRNAs (miRNAs) in human malignancies has been well recognized. Here, we report that the expression of microRNA-210 (miR-210) is down-regulated in human esophageal squamous cell carcinoma and derived cell lines. Marked decreases in the level of miR-210 were observed especially in poorly differentiated carcinomas. We found that miR-210 inhibits cancer cell survival and proliferation by inducing cell death and cell cycle arrest in G(1)/G(0) and G(2)/M. Finally, we identified fibroblast growth factor receptor-like 1 (FGFRL1) as a target of miR-210 in esophageal squamous cell carcinoma and demonstrated that FGFRL1 accelerates cancer cell proliferation by preventing cell cycle arrest in G(1)/G(0). Taken together, our findings show an important role for miR-210 as a tumor-suppressive microRNA with effects on cancer cell proliferation.

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    • "So far, we identified FgfrL1 protein only if the corresponding cDNA was over-expressed in cell culture from a strong CMV promoter [8]. This fact raises doubts about several recent reports, which detected FgfrL1 protein with polyclonal antibodies in mouse kidney [7], rat diaphragm [25], epithelium of human bladder [26] and stroma of esophageal tumors [27]. It is therefore conceivable that commercial polyclonal antibodies cross-react with unrelated proteins. "
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    ABSTRACT: FgfrL1 is the fifth member of the fibroblast growth factor receptor (Fgfr) family. Studies with FgfrL1 deficient mice have demonstrated that the gene plays an important role during embryonic development. FgfrL1 knock-out mice die at birth as they have a malformed diaphragm and lack metanephric kidneys. Similar to the classical Fgfrs, the FgfrL1 protein contains an extracellular part composed of three Ig-like domains that interact with Fgf ligands and heparin. However, the intracellular part of FgfrL1 is not related to the classical receptors and does not possess any tyrosine kinase activity. Curiously enough, the amino acid sequence of this domain is barely conserved among different species, with the exception of three motifs, namely a dileucine peptide, a tandem tyrosine-based motif YXXΦ and a histidine-rich sequence. To investigate the function of the intracellular domain of FgfrL1, we have prepared genetically modified mice that lack the three conserved sequence motifs, but instead contain a GFP cassette (FgfrL1ΔC-GFP). To our surprise, homozygous FgfrL1ΔC-GFP knock-in mice are viable, fertile and phenotypically normal. They do not exhibit any alterations in the diaphragm or the kidney, except for a slight reduction in the number of glomeruli that does not appear to affect life expectancy. In addition, the pancreas of both FgfrL1ΔC-GFP knock-in and FgfrL1 knock-out mice do not show any disturbances in the production of insulin, in contrast to what has been suggested by recent studies. Thus, the conserved motifs of the intracellular FgfrL1 domain are dispensable for organogenesis and normal life. We conclude that the extracellular domain of the protein must conduct the vital functions of FgfrL1.
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    • "Most evidence showed that miR-210 was up-regulated in many solid tumors, including breast cancer [16,78-80], head and neck cancer [17,76], pancreatic cancer [81-83], lung cancer [55,84-87], renal cancer [23,88,89], lymphoma [90], osteosarcoma [91], esophageal cancer [92] as well as ovarian cancer [93]. There are also some inconsistent evidence that miR-210 was deleted in some cases of ovarian cancer [18], and was down-regulated in some cases of esophageal cancer [26], exhibiting the complexity and heterogeneity of cancer. "
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