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      Long non-coding RNAs in Oral squamous cell carcinoma: biologic function, mechanisms and clinical implications

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          Abstract

          There is growing evidence that regions of the genome that cannot encode proteins play an important role in diseases. These regions are usually transcribed into long non-coding RNAs (lncRNAs). LncRNAs, little or no coding potential, are defined as capped transcripts longer than 200 nucleotides. New sequencing technologies have shown that a large number of aberrantly expressed lncRNAs are associated with multiple cancer types and indicated they have emerged as an important class of pervasive genes during the development and progression of cancer. However, the underlying mechanism in cancer is still unknown. Therefore, it is necessary to elucidate the lncRNA function. Notably, many lncRNAs dysregulation are associated with Oral squamous cell carcinoma (OSCC) and affect various aspects of cellular homeostasis, including proliferation, survival, migration or genomic stability. This review expounds the up- or down-regulation of lncRNAs in OSCC and the molecular mechanisms by which lncRNAs perform their function in the malignant cell. Finally, the potential of lncRNAs as non-invasive biomarkers for OSCC diagnosis are also described. LncRNAs hold promise as prospective novel therapeutic targets, but more research is needed to gain a better understanding of their biologic function.

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          Most cited references 139

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          An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans.

          Two small temporal RNAs (stRNAs), lin-4 and let-7, control developmental timing in Caenorhabditis elegans. We find that these two regulatory RNAs are members of a large class of 21- to 24-nucleotide noncoding RNAs, called microRNAs (miRNAs). We report on 55 previously unknown miRNAs in C. elegans. The miRNAs have diverse expression patterns during development: a let-7 paralog is temporally coexpressed with let-7; miRNAs encoded in a single genomic cluster are coexpressed during embryogenesis; and still other miRNAs are expressed constitutively throughout development. Potential orthologs of several of these miRNA genes were identified in Drosophila and human genomes. The abundance of these tiny RNAs, their expression patterns, and their evolutionary conservation imply that, as a class, miRNAs have broad regulatory functions in animals.
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            GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer.

            Effective control of both cell survival and cell proliferation is critical to the prevention of oncogenesis and to successful cancer therapy. Using functional expression cloning, we have identified GAS5 (growth arrest-specific transcript 5) as critical to the control of mammalian apoptosis and cell population growth. GAS5 transcripts are subject to complex post-transcriptional processing and some, but not all, GAS5 transcripts sensitize mammalian cells to apoptosis inducers. We have found that, in some cell lines, GAS5 expression induces growth arrest and apoptosis independently of other stimuli. GAS5 transcript levels were significantly reduced in breast cancer samples relative to adjacent unaffected normal breast epithelial tissues. The GAS5 gene has no significant protein-coding potential but expression encodes small nucleolar RNAs (snoRNAs) in its introns. Taken together with the recent demonstration of tumor suppressor characteristics in the related snoRNA U50, our observations suggest that such snoRNAs form a novel family of genes controlling oncogenesis and sensitivity to therapy in cancer.
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              CRISPR–Cas9 Structures and Mechanisms

              Many bacterial clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated (Cas) systems employ the dual RNA–guided DNA endonuclease Cas9 to defend against invading phages and conjugative plasmids by introducing site-specific double-stranded breaks in target DNA. Target recognition strictly requires the presence of a short protospacer adjacent motif (PAM) flanking the target site, and subsequent R-loop formation and strand scission are driven by complementary base pairing between the guide RNA and target DNA, Cas9–DNA interactions, and associated conformational changes. The use of CRISPR–Cas9 as an RNA-programmable DNA targeting and editing platform is simplified by a synthetic single-guide RNA (sgRNA) mimicking the natural dual trans-activating CRISPR RNA (tracrRNA)–CRISPR RNA (crRNA) structure. This review aims to provide an in-depth mechanistic and structural understanding of Cas9-mediated RNA-guided DNA targeting and cleavage. Molecular insights from biochemical and structural studies provide a framework for rational engineering aimed at altering catalytic function, guide RNA specificity, and PAM requirements and reducing off-target activity for the development of Cas9-based therapies against genetic diseases.
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                Author and article information

                Contributors
                zhanglei6551@126.com
                zzxh2015@126.com
                gege8510@126.com
                812872758@qq.com
                aydchenran@163.com
                +86 551 62776259 , aydjy@outlook.com
                +86 551 65172131 , xutao@ahmu.edu.cn
                Journal
                Mol Cancer
                Mol. Cancer
                Molecular Cancer
                BioMed Central (London )
                1476-4598
                27 May 2019
                27 May 2019
                2019
                : 18
                Affiliations
                [1 ]ISNI 0000 0000 9490 772X, GRID grid.186775.a, College & Hospital of Stomatology, , Anhui Medical University, Key Lab. of Oral Diseases Research of Anhui Province, ; Hefei, 230032 China
                [2 ]ISNI 0000 0000 9490 772X, GRID grid.186775.a, Department of Periodontology, College and Hospital of Stomatology, , Anhui Medical University, ; Hefei, 230032 Anhui Province China
                [3 ]ISNI 0000 0000 9490 772X, GRID grid.186775.a, School of Stomatology, , Anhui Medical University, ; Hefei, 230032 Anhui Province China
                [4 ]ISNI 0000 0000 9490 772X, GRID grid.186775.a, Outpatient Department of Binhu District, College and Hospital of Stomatology, , Anhui Medical University, ; Hefei, 230601 Anhui Province China
                [5 ]GRID grid.452799.4, Department of Stomatology, , The Fourth Affiliated Hospital of Anhui Medical University, ; 372 Tunxi Road, Hefei, 230000 Anhui Province China
                [6 ]ISNI 0000 0000 9490 772X, GRID grid.186775.a, School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, , Anhui Medical University, ; 81 Meishan Road, Hefei, 230032 Anhui Province China
                [7 ]ISNI 0000 0000 9490 772X, GRID grid.186775.a, Institute for Liver Diseases of Anhui Medical University, , Anhui Medical University, ; 81 Meishan Road, Hefei, 230032 Anhui Province China
                Article
                1021
                10.1186/s12943-019-1021-3
                6535863
                31133028
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81700522
                Award ID: 81470003
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100009558, University Natural Science Research Project of Anhui Province;
                Award ID: KJ2018A0203
                Award Recipient :
                Funded by: the fund of Anhui medical university doctoral start research
                Award ID: XJ201706
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003995, Natural Science Foundation of Anhui Province;
                Award ID: 1508085MH187
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2019

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