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      Potential Value of miR-221/222 as Diagnostic, Prognostic, and Therapeutic Biomarkers for Diseases

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          Abstract

          microRNAs (miRNAs) are short non-coding RNAs that regulate gene expression by base pairing with their target messenger RNAs. Dysregulation of miRNAs is involved in the pathological initiation and progression of many human diseases. miR-221 and miR-222 (miR-221/222) are two highly homologous miRNAs, and they are significantly overexpressed in several types of human diseases. Silencing miR-221/222 could represent a promising approach for therapeutic studies. In the present review, we will describe the potential value of miR-221/222 as diagnostic, prognostic, and therapeutic biomarkers in various diseases including cancer and inflammatory diseases.

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          Most cited references76

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          Molecular basis for the recognition of primary microRNAs by the Drosha-DGCR8 complex.

          The Drosha-DGCR8 complex initiates microRNA maturation by precise cleavage of the stem loops that are embedded in primary transcripts (pri-miRNAs). Here we propose a model for this process that is based upon evidence from both computational and biochemical analyses. A typical metazoan pri-miRNA consists of a stem of approximately 33 bp, with a terminal loop and flanking segments. The terminal loop is unessential, whereas the flanking ssRNA segments are critical for processing. The cleavage site is determined mainly by the distance (approximately 11 bp) from the stem-ssRNA junction. Purified DGCR8, but not Drosha, interacts with pri-miRNAs both directly and specifically, and the flanking ssRNA segments are vital for this binding to occur. Thus, DGCR8 may function as the molecular anchor that measures the distance from the dsRNA-ssRNA junction. Our current study thus facilitates the prediction of novel microRNAs and will assist in the rational design of small hairpin RNAs for RNA interference.
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            MicroRNA-221/222 confers tamoxifen resistance in breast cancer by targeting p27Kip1.

            We explored the role of microRNAs (miRNAs) in acquiring resistance to tamoxifen, a drug successfully used to treat women with estrogen receptor-positive breast cancer. miRNA microarray analysis of MCF-7 cell lines that are either sensitive (parental) or resistant (4-hydroxytamoxifen-resistant (OHT(R))) to tamoxifen showed significant (>1.8-fold) up-regulation of eight miRNAs and marked down-regulation (>50%) of seven miRNAs in OHT(R) cells compared with parental MCF-7 cells. Increased expression of three of the most promising up-regulated (miR-221, miR-222, and miR-181) and down-regulated (miR-21, miR-342, and miR-489) miRNAs was validated by real-time reverse transcription-PCR. The expression of miR-221 and miR-222 was also significantly (2-fold) elevated in HER2/neu-positive primary human breast cancer tissues that are known to be resistant to endocrine therapy compared with HER2/neu-negative tissue samples. Ectopic expression of miR-221/222 rendered the parental MCF-7 cells resistant to tamoxifen. The protein level of the cell cycle inhibitor p27(Kip1), a known target of miR-221/222, was reduced by 50% in OHT(R) cells and by 28-50% in miR-221/222-overexpressing MCF-7 cells. Furthermore, overexpression of p27(Kip1) in the resistant OHT(R) cells caused enhanced cell death when exposed to tamoxifen. This is the first study demonstrating a relationship between miR-221/222 expression and HER2/neu overexpression in primary breast tumors that are generally resistant to tamoxifen therapy. This finding also provides the rationale for the application of altered expression of specific miRNAs as a predictive tamoxifen-resistant breast cancer marker.
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              miR-221 overexpression contributes to liver tumorigenesis.

              MicroRNA (miRNAs) are negative regulators of gene expression and can function as tumor suppressors or oncogenes. Expression patterns of miRNAs and their role in the pathogenesis of hepatocellular carcinoma (HCC) are still poorly understood. We profiled miRNA expression in tissue samples (104 HCC, 90 adjacent cirrhotic livers, 21 normal livers) as well as in 35 HCC cell lines. A set of 12 miRNAs (including miR-21, miR-221/222, miR-34a, miR-519a, miR-93, miR-96, and let-7c) was linked to disease progression from normal liver through cirrhosis to full-blown HCC. miR-221/222, the most up-regulated miRNAs in tumor samples, are shown to target the CDK inhibitor p27 and to enhance cell growth in vitro. Conversely, these activities can be efficiently inhibited by an antagomiR specific for miR-221. In addition, we show, using a mouse model of liver cancer, that miR-221 overexpression stimulates growth of tumorigenic murine hepatic progenitor cells. Finally, we identified DNA damage-inducible transcript 4 (DDIT4), a modulator of mTOR pathway, as a bona fide target of miR-221. Taken together, these data reveal an important contribution for miR-221 in hepatocarcinogenesis and suggest a role for DDIT4 dysregulation in this process. Thus, the use of synthetic inhibitors of miR-221 may prove to be a promising approach to liver cancer treatment.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                16 February 2017
                2017
                : 8
                : 56
                Affiliations
                [1] 1Shanghai Jiao Tong University Affiliated Sixth People’s Hospital , Shanghai, China
                [2] 2Shanghai University of Medicine & Health, Shanghai Sixth People’s Hospital East Campus , Shanghai, China
                [3] 3School of Pharmacy, Shanghai Jiao Tong University , Shanghai, China
                [4] 4Department of Neurology, Jinshan Hospital, Fudan University , Shanghai, China
                Author notes

                Edited by: Kai Fang, University of California Los Angeles, USA

                Reviewed by: Francesca Lovat, Ohio State University, USA; Satoshi Fukushima, Kumamoto University, Japan

                *Correspondence: Yinghui Chen, cyh1973131@ 123456163.com ; Cunyi Fan, fancunyi888@ 123456163.com ; Weien Yuan, yuanweien@ 123456126.com

                These authors have contributed equally to this work.

                Specialty section: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2017.00056
                5311065
                28261196
                062a12e9-c2d5-4ef2-a1b5-f9cb9c06bd2f
                Copyright © 2017 Song, Ouyang, Che, Li, Zhao, Yang, Zhao, Chen, Fan and Yuan.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 21 October 2016
                : 13 January 2017
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 107, Pages: 9, Words: 8099
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 81570992, and 81571261
                Funded by: Natural Science Foundation of Shanghai 10.13039/100007219
                Award ID: 15ZR1432500
                Categories
                Immunology
                Mini Review

                Immunology
                micrornas,mir-221/222,diseases,diagnosis,prognosis,therapy,biomarker
                Immunology
                micrornas, mir-221/222, diseases, diagnosis, prognosis, therapy, biomarker

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