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      Gastric Carcinogenesis in the miR-222/221 Transgenic Mouse Model

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          Abstract

          Purpose

          MicroRNAs (miRNAs) regulate various cellular functions, including development, cell proliferation, apoptosis, and tumorigenesis. Different signatures associated with various tissue types, diagnosis, progression, prognosis, staging, and treatment response have been identified by miRNA expression profiling of human tumors. miRNAs function as oncogenes or as tumor suppressors. The relationship between gastric cancer and miRNA garnered attention due to the high incidence of gastric cancer in Asian countries. miR-222/221 expression increases in gastric tumor tissues. The oncogenic effect of miR-222/221 was previously determined in functional studies and xenograft models. In this study, transgenic mice over-expressing miR-222/221 were generated to confirm the effect of miR-222/221 on gastric carcinogenesis.

          Materials and Methods

          At 6 weeks of age, 65 transgenic mice and 53 wild-type mice were given drinking water containing N-nitroso- N-methylurea (MNU) for 5 alternating weeks to induce gastric cancer. The mice were euthanized at 36 weeks of age and histologic analysis was performed.

          Results

          Hyperplasia was observed in 3.77% of the wild-type mice and in 18.46% of the transgenic mice (p=0.020). Adenoma was observed in 20.75% of the wild-type mice and 26.15% of the transgenic mice (p=0.522). Carcinoma was observed in 32.08% of the wild-type mice and 41.54% of the transgenic mice (p=0.341). The frequency of hyperplasia, adenoma, and carcinoma was higher in transgenic mice, but the difference was statistically significant only in hyperplasia.

          Conclusion

          These results suggest that hyperplasia, a gastric pre-cancerous lesion, is associated with miR-222/221 expression but miR-222/221 expression does not affect tumorigenesis itself.

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          Most cited references 25

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          Global cancer statistics, 2002.

           D Parkin,  F Bray,  J Ferlay (2005)
          Estimates of the worldwide incidence, mortality and prevalence of 26 cancers in the year 2002 are now available in the GLOBOCAN series of the International Agency for Research on Cancer. The results are presented here in summary form, including the geographic variation between 20 large "areas" of the world. Overall, there were 10.9 million new cases, 6.7 million deaths, and 24.6 million persons alive with cancer (within three years of diagnosis). The most commonly diagnosed cancers are lung (1.35 million), breast (1.15 million), and colorectal (1 million); the most common causes of cancer death are lung cancer (1.18 million deaths), stomach cancer (700,000 deaths), and liver cancer (598,000 deaths). The most prevalent cancer in the world is breast cancer (4.4 million survivors up to 5 years following diagnosis). There are striking variations in the risk of different cancers by geographic area. Most of the international variation is due to exposure to known or suspected risk factors related to lifestyle or environment, and provides a clear challenge to prevention.
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            Most mammalian mRNAs are conserved targets of microRNAs.

            MicroRNAs (miRNAs) are small endogenous RNAs that pair to sites in mRNAs to direct post-transcriptional repression. Many sites that match the miRNA seed (nucleotides 2-7), particularly those in 3' untranslated regions (3'UTRs), are preferentially conserved. Here, we overhauled our tool for finding preferential conservation of sequence motifs and applied it to the analysis of human 3'UTRs, increasing by nearly threefold the detected number of preferentially conserved miRNA target sites. The new tool more efficiently incorporates new genomes and more completely controls for background conservation by accounting for mutational biases, dinucleotide conservation rates, and the conservation rates of individual UTRs. The improved background model enabled preferential conservation of a new site type, the "offset 6mer," to be detected. In total, >45,000 miRNA target sites within human 3'UTRs are conserved above background levels, and >60% of human protein-coding genes have been under selective pressure to maintain pairing to miRNAs. Mammalian-specific miRNAs have far fewer conserved targets than do the more broadly conserved miRNAs, even when considering only more recently emerged targets. Although pairing to the 3' end of miRNAs can compensate for seed mismatches, this class of sites constitutes less than 2% of all preferentially conserved sites detected. The new tool enables statistically powerful analysis of individual miRNA target sites, with the probability of preferentially conserved targeting (P(CT)) correlating with experimental measurements of repression. Our expanded set of target predictions (including conserved 3'-compensatory sites), are available at the TargetScan website, which displays the P(CT) for each site and each predicted target.
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              The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14.

              lin-4 is essential for the normal temporal control of diverse postembryonic developmental events in C. elegans. lin-4 acts by negatively regulating the level of LIN-14 protein, creating a temporal decrease in LIN-14 protein starting in the first larval stage (L1). We have cloned the C. elegans lin-4 locus by chromosomal walking and transformation rescue. We used the C. elegans clone to isolate the gene from three other Caenorhabditis species; all four Caenorhabditis clones functionally rescue the lin-4 null allele of C. elegans. Comparison of the lin-4 genomic sequence from these four species and site-directed mutagenesis of potential open reading frames indicated that lin-4 does not encode a protein. Two small lin-4 transcripts of approximately 22 and 61 nt were identified in C. elegans and found to contain sequences complementary to a repeated sequence element in the 3' untranslated region (UTR) of lin-14 mRNA, suggesting that lin-4 regulates lin-14 translation via an antisense RNA-RNA interaction.
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                Author and article information

                Journal
                Cancer Res Treat
                Cancer Res Treat
                CRT
                Cancer Research and Treatment : Official Journal of Korean Cancer Association
                Korean Cancer Association
                1598-2998
                2005-9256
                January 2017
                23 June 2016
                : 49
                : 1
                : 150-160
                Affiliations
                [1 ]Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
                [2 ]Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
                [3 ]Center for RNA Research, Institute for Basic Science, Korea School of Biological Sciences, Seoul National University, Seoul, Korea
                [4 ]Department of Biochemistry, Chonnam National University Medical School, Gwangju, Korea
                [5 ]Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, Kyungpook National University School of Medicine, Daegu, Korea
                [6 ]Department of Experimental Animal Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea
                [7 ]Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
                [8 ]Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, Seoul, Korea
                [9 ]Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
                Author notes
                Correspondence: Han-Kwang Yang, MD, PhD  Department of Surgery, Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea  Tel: 82-2-2072-0100 Fax: 82-2-3672-0047 E-mail: hkyang@ 123456snu.ac.kr
                [*]

                Boram Choi and Jieun Yu contributed equally to this work.

                crt-2015-462
                10.4143/crt.2015.462
                5266385
                27338035
                Copyright © 2017 by the Korean Cancer Association

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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