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      Circulating Exosomal microRNAs as Biomarkers of Colon Cancer

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          Abstract

          Purpose

          Exosomal microRNAs (miRNAs) have been attracting major interest as potential diagnostic biomarkers of cancer. The aim of this study was to characterize the miRNA profiles of serum exosomes and to identify those that are altered in colorectal cancer (CRC). To evaluate their use as diagnostic biomarkers, the relationship between specific exosomal miRNA levels and pathological changes of patients, including disease stage and tumor resection, was examined.

          Experimental Design

          Microarray analyses of miRNAs in exosome-enriched fractions of serum samples from 88 primary CRC patients and 11 healthy controls were performed. The expression levels of miRNAs in the culture medium of five colon cancer cell lines were also compared with those in the culture medium of a normal colon-derived cell line. The expression profiles of miRNAs that were differentially expressed between CRC and control sample sets were verified using 29 paired samples from post-tumor resection patients. The sensitivities of selected miRNAs as biomarkers of CRC were evaluated and compared with those of known tumor markers (CA19-9 and CEA) using a receiver operating characteristic analysis. The expression levels of selected miRNAs were also validated by quantitative real-time RT-PCR analyses of an independent set of 13 CRC patients.

          Results

          The serum exosomal levels of seven miRNAs (let-7a, miR-1229, miR-1246, miR-150, miR-21, miR-223, and miR-23a) were significantly higher in primary CRC patients, even those with early stage disease, than in healthy controls, and were significantly down-regulated after surgical resection of tumors. These miRNAs were also secreted at significantly higher levels by colon cancer cell lines than by a normal colon-derived cell line. The high sensitivities of the seven selected exosomal miRNAs were confirmed by a receiver operating characteristic analysis.

          Conclusion

          Exosomal miRNA signatures appear to mirror pathological changes of CRC patients and several miRNAs are promising biomarkers for non-invasive diagnosis of the disease.

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          Most cited references 37

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          Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.

           K Livak,  T Schmittgen (2001)
          The two most commonly used methods to analyze data from real-time, quantitative PCR experiments are absolute quantification and relative quantification. Absolute quantification determines the input copy number, usually by relating the PCR signal to a standard curve. Relative quantification relates the PCR signal of the target transcript in a treatment group to that of another sample such as an untreated control. The 2(-Delta Delta C(T)) method is a convenient way to analyze the relative changes in gene expression from real-time quantitative PCR experiments. The purpose of this report is to present the derivation, assumptions, and applications of the 2(-Delta Delta C(T)) method. In addition, we present the derivation and applications of two variations of the 2(-Delta Delta C(T)) method that may be useful in the analysis of real-time, quantitative PCR data. Copyright 2001 Elsevier Science (USA).
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            Global cancer statistics.

            The global burden of cancer continues to increase largely because of the aging and growth of the world population alongside an increasing adoption of cancer-causing behaviors, particularly smoking, in economically developing countries. Based on the GLOBOCAN 2008 estimates, about 12.7 million cancer cases and 7.6 million cancer deaths are estimated to have occurred in 2008; of these, 56% of the cases and 64% of the deaths occurred in the economically developing world. Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females, accounting for 23% of the total cancer cases and 14% of the cancer deaths. Lung cancer is the leading cancer site in males, comprising 17% of the total new cancer cases and 23% of the total cancer deaths. Breast cancer is now also the leading cause of cancer death among females in economically developing countries, a shift from the previous decade during which the most common cause of cancer death was cervical cancer. Further, the mortality burden for lung cancer among females in developing countries is as high as the burden for cervical cancer, with each accounting for 11% of the total female cancer deaths. Although overall cancer incidence rates in the developing world are half those seen in the developed world in both sexes, the overall cancer mortality rates are generally similar. Cancer survival tends to be poorer in developing countries, most likely because of a combination of a late stage at diagnosis and limited access to timely and standard treatment. A substantial proportion of the worldwide burden of cancer could be prevented through the application of existing cancer control knowledge and by implementing programs for tobacco control, vaccination (for liver and cervical cancers), and early detection and treatment, as well as public health campaigns promoting physical activity and a healthier dietary intake. Clinicians, public health professionals, and policy makers can play an active role in accelerating the application of such interventions globally.
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              Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells.

              Exosomes are vesicles of endocytic origin released by many cells. These vesicles can mediate communication between cells, facilitating processes such as antigen presentation. Here, we show that exosomes from a mouse and a human mast cell line (MC/9 and HMC-1, respectively), as well as primary bone marrow-derived mouse mast cells, contain RNA. Microarray assessments revealed the presence of mRNA from approximately 1300 genes, many of which are not present in the cytoplasm of the donor cell. In vitro translation proved that the exosome mRNAs were functional. Quality control RNA analysis of total RNA derived from exosomes also revealed presence of small RNAs, including microRNAs. The RNA from mast cell exosomes is transferable to other mouse and human mast cells. After transfer of mouse exosomal RNA to human mast cells, new mouse proteins were found in the recipient cells, indicating that transferred exosomal mRNA can be translated after entering another cell. In summary, we show that exosomes contain both mRNA and microRNA, which can be delivered to another cell, and can be functional in this new location. We propose that this RNA is called "exosomal shuttle RNA" (esRNA).
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                4 April 2014
                : 9
                : 4
                Affiliations
                [1 ]Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan
                [2 ]Division of Cancer Development System, National Cancer Center Research Institute, Tokyo, Japan
                [3 ]Department of Gastroenterology, The University of Tokyo Hospital, Tokyo, Japan
                [4 ]Laboratory for Medical Engineering, Division of Materials and Chemical Engineering, Graduate School of Engineering, Yokohama National University, Kanagawa, Japan
                [5 ]Gastrointestinal Oncology Division, National Cancer Center Hospital, Tokyo, Japan
                [6 ]Division of Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
                [7 ]NTT Medical Center Tokyo, Tokyo, Japan
                [8 ]Shionogi & Co., Ltd., Osaka, Japan
                [9 ]Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Barcelona, Spain
                Kanazawa University, Japan
                Author notes

                Competing Interests: Hideki Ohta, Hiroyuki Okamoto and Hikaru Sonoda, are employees of Shionogi & Co., Ltd. Shionogi & Co., Ltd. has an exclusive license for several miRNAs presented in this work. Shionogi & Co., Ltd. has applied for a patent (WO2011/040525) for the development of these miRNAs as diagnostic markers. There are no further patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: NT. Performed the experiments: HOK MI DK H. Ohta H. Okamoto HS NT. Analyzed the data: HOK MI NT. Contributed reagents/materials/analysis tools: YH YY KF TG MW HN JY TK. Wrote the paper: HOK NT.

                PONE-D-13-47479
                10.1371/journal.pone.0092921
                3976275
                24705249

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Counts
                Pages: 9
                Funding
                Funding provided by The Advanced Research for Medical Products Mining Program of the National Institute of Biomedical Innovation (NIBIO)(08-02), http://www.nibio.go.jp; Grant-in-Aids from the Ministry of Health, Labor and Welfare (13802015), http://www.mhlw.go.jp/; Grant-in-Aids from the Ministry of Education, Culture, Sports & Technology of Japan (13314780), http://www.jsps.go.jp/; National Cancer Center Research and Development Fund (23-B-08), http://www.ncc.go.jp. National Cancer Center Biobank is supported by National Cancer Center Research and Development Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and life sciences
                Biochemistry
                Biomarkers
                Nucleic Acids
                RNA
                Genetics
                Epigenetics
                RNA interference
                Gene Expression
                Medicine and Health Sciences
                Diagnostic Medicine
                Epidemiology
                Biomarker Epidemiology
                Oncology
                Cancers and Neoplasms
                Carcinomas
                Adenocarcinomas
                Colon Adenocarcinoma
                Gastrointestinal Tumors
                Cancer Detection and Diagnosis
                Cancer Risk Factors
                Pathology and Laboratory Medicine

                Uncategorized

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