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: 4.6). 11/2010; 286(1):420-8. DOI: 10.1074/jbc.M110.170852
Source: PubMed

ABSTRACT 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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    ABSTRACT: Background We previously reported that the expression of fibroblast growth factor receptor-like 1 (FGFRL1) was associated with the progression of esophageal squamous cell carcinoma (ESCC). However, the clinical roles of FGFR1, FGFR2, FGFR3, and FGFR4 in ESCC have not yet been examined in detail. Furthermore, it currently remains unclear why FGFRL1 is a prognostic factor for ESCC. Materials and methods A squamous cell carcinoma tissue microarray established in Toyama University was used to evaluate the expression of the 4 FGFRs. Sixty-nine ESCC specimens were obtained from patients who had undergone surgery between 1990 and 2008. The immunohistochemical results obtained herein were compared to those for FGFRL1 from our previous study. We also determined whether FGFRL1 bound to other FGFRs that were selected using the tissue microarray analysis. Results The frequency of different FGFR overexpression combinations revealed that FGFRL1, FGFR1, and FGFR4 were the predominant types. In contrast to FGFRL1, no association was observed between the expression of each FGFR and patient prognosis. Regarding the combination analysis, patients that co-expressed FGFRL1 and FGFR1 had the worst prognosis, while patients who tested negative for the expression of both FGFRL1 and FGFR4 had the best prognosis. The results of the proximity ligation assay demonstrated that FGFRL1 bound to FGFR1 and FGFR4. Conclusions Of the 5 FGFRs examined, the expression of FGFRL1 was the main prognostic factor in ESCC patients. FGFR1 and FGFR4 may be sub-driving factors of ESCC as well as the main targets of the heterodimer of FGFRL1.
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    ABSTRACT: To investigate the expression of miR-210 and the role it plays in the cell cycle to regulate radioresistance in oesophageal squamous cell carcinoma (ESCC). MiR-210 expression was evaluated in 37 pairs of ESCC tissues and matched para-tumorous normal oesophageal tissues from surgical patients who had not received neoadjuvant therapy, and in the cells of two novel radioresistant cell lines, TE-1R and Eca-109R, using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The transient up-regulation of miR-210 expression in TE-1R and Eca-109R cells was studied using liposomes and was confirmed using qRT-PCR. The rate of cell survival after a series of radio-treatment doses was evaluated using the clone formation assay. Flow cytometry was used to detect the changes to the cell cycle patterns due to radiation treatment. RT-PCR and Western blot were used to detect the expression of ataxia telangiectasia mutated (ATM) and DNA dependent protein kinase (DNA-PKcs) after irradiation, and the cell sphere formation assay was used to evaluate the proliferative ability of the cancer stem-like cells. The level of miR-210 expression was significantly decreased, by 21.3% to 97.2%, with the average being 39.2% ± 16.1%, in the ESCC tissues of most patients (81.1%, 30 of 37 vs patients with high miR-210 expression, P < 0.05). A low level of expression of miR-210 was correlated with a poorly differentiated pathological type (P < 0.01) but was not correlated with the T-stage or lymph node infiltration (both P > 0.05). Early local recurrences (< 18 mo, n = 19) after radiotherapy were significantly related with low miR-210 expression (n = 13, P < 0.05). The level of miR-210 was decreased by approximately 73% (vs TE-1, 0.27 ± 0.10, P < 0.01) in the established radioresistant TE-IR cell line and by 52% (vs Eca-109, 0.48 ± 0.17, P < 0.05) in the corresponding Eca-109R line. Transient transfection with a miR-210 precursor increased the level of miR-210 expression, leading to a significant increase in cell survival after radiotherapy (P < 0.05). Twenty-four hours after radiation, the proportion of pmiR-210 cells in S phase was increased (vs control cells, 30.4% ± 0.4%, and vs untreated TE-1R cells, 23.3% ± 0.7%, P < 0.05 for both). The levels of DNA-PKcs (0.21 ± 0.07) and ATM (0.12 ± 0.03, P < 0.05) proteins were significantly lower in the PmiR-210 cells than in control cells, but no differences were found in the levels of the corresponding mRNAs in the two cell types (P > 0.05 for all). Exogenous miR-210 expression decreased the diameter of pmiR-210 cell spheres (vs control cells, 0.60 ± 0.14, P < 0.05). MiR-210 expression is negatively correlated with the pathological type and the local survival rate after radiotherapy, and high expression of miR-210 may reverse the radioresistance of ESCC stem-like cells.
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    ABSTRACT: Accurate assessment of prognosis of clear cell renal cell carcinoma (ccRCC) is key in optimizing management plans to fit individual patient needs. miRNAs are short noncoding single-stranded RNAs that control the expression of target genes and may act as cancer biomarkers. We analyzed the expression of miR-210 in 276 cases of primary ccRCC and compared its expression in 40 pairs of adjacent normal and cancerous tissues. We assessed its expression in primary and metastatic tumors, in the common RCC subtypes, and the benign oncocytoma. The results were validated with an independent data set from The Cancer Genome Atlas. miR-210 was significantly overexpressed in ccRCC compared with normal kidney. miR-210(+) patients had a statistically higher chance of disease recurrence [hazard ratio (HR), 1.82; P = 0.018] and shorter overall survival (HR, 2.46; P = 0.014). In multivariate analysis, miR-210 lost its statistically significant association with shorter disease-free survival and overall survival after adjusting for tumor size and tumor, node, metastasis stage. Papillary RCC showed comparable miR-210 overexpression, whereas decreased up-regulation was seen in chromophobe RCC and oncocytoma. A number of predicted targets that might be involved in carcinogenesis and aggressive tumor behavior were identified. miR-210 is a potential therapeutic target and independent marker of poor prognosis of ccRCC. Copyright © 2014 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.
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