Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
ReviewLncRNA: A link between RNA and cancer
Introduction
Ever since the proposal of central dogma of molecular biology in 1961 [1], RNA was considered as an intermediate between DNA and protein. The central dogma has provided us a simplified framework of how genetic information is translated into diversity of biological process. Later on, these intermediate RNAs (mRNAs) are found to be just a small fraction of the total RNA population, as the discovery of non-coding RNAs (ncRNAs). These ncRNAs function directly as structural, catalytic or regulatory RNAs, rather than encoding proteins [2], [3], [4]. Up to now, there are still no satisfactory classifications for these transcripts. Based on the expression and function, ncRNA can be classified as groups including ‘housekeeping’ ncRNAs (ribosomal RNA, transfer RNA, small nuclear RNA and small nucleolar RNA), some lowly expressed regulatory ncRNAs and several other poorly characterized types of ncRNAs [5]. According to their sizes, the regulatory ncRNAs can be further classified as small ncRNAs (< 200 bps, e.g. miRNAs, siRNAs, and piRNAs) and long ncRNAs (lncRNAs) (> 200 bps, e.g. lincRNAs, macroRNAs) [5].
During the past decades of RNA biology study, multiple lncRNAs have been identified, such as Xist [6] and H19 [7], which hold as milestones in lncRNA biology. With the advent of advanced sequencing technologies and findings from large-scale consortia focused on characterizing functional genomic elements, such as ENCODE (encyclopedia of DNA elements), more and more lncRNAs are being identified and awaited for functional validation. According to the recent data by ENCODE Project Consortium in 2012, there are about 9640 long non-coding RNA (lncRNA) loci in human genome [8], [9], while the number continues to grow. All of these have shed light on the promising future of lncRNA study. LncRNAs have been found to be involved in the regulation at chromatin organization, transcriptional, and post-transcriptional levels [10], revolutionizing our understanding of the architecture, activity and regulation of the eukaryotic genome. LncRNAs have added another layer of genome complexity; meanwhile they provide alternative explanation that the diversity of biology is not solely on the protein coding genes, their splicing or posttranslational regulation.
LncRNAs have emerged as an essential regulator in almost all aspects of biology. Accumulating evidence suggests that lncRNAs play an important role in tumorigenesis [11]. In this review, we will briefly review the structure and function of lncRNAs, and then emphasize their aberrant expression and their functional roles in cancer development, diagnosis and therapy.
Section snippets
Genomic distribution of lncRNA and their expression
Before we discuss the role of lncRNAs in cancer, we first need to refer their structure, expression and function under physiological conditions. According to a recent manual annotation of lncRNAs, there should be about 9640 lncRNAs, approximately half of the protein encoding genes [8], [9] According to LNCipedia 2.0, the latest version of this long non-coding RNA database, there are already 32,183 human annotated lncRNAs. Currently, few lncRNAs are functionally validated [12]. LncRNAs are
LncRNAs in cancer
In a molecular perspective, cancer is a genetic disease due to aberrant expression and function of tumor suppressor and oncogenic genes. Besides the canonical protein encoding genes, more and more lncRNAs are found to be oncogenes or tumor suppressors, adding a new layer of complexity to the molecular architecture of human cancers (Table 2). Here we will focus on how these lncRNAs are aberrantly expressed in cancers and their contribution to cancer hallmarks.
LncRNAs in cancer diagnosis and therapy
Identification and characterization of the detailed lncRNAs involved in the initiation and progression of different types of cancers would be finally beneficial for cancer diagnosis and therapy. Although nearly hundreds of oncogenes, tumor suppressor genes and some diagnostic biomarker have been reported in the past decades, cancer remains the big hurdle of health. It raises the question whether these protein markers and targets really represent the real case of cancer development. And it thus
Concluding remarks and future direction
The six acquired capabilities (sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis)—the hallmarks of cancer—have provided a useful conceptual framework for understanding the complex biology of cancer [77]. Elucidation of the molecular networks by which these hallmark capabilities are acquired would eventually lead to the victory of the combat against cancer. It is
Conflict of interest
The authors declare that they have no conflict of interest.
Acknowledgments
This study was funded by National Science Foundation of China, NSFC31100979, NSFC81170149, and NSFC81101050.
References (153)
- et al.
Noncoding RNA transcription beyond annotated genes
Curr. Opin. Genet. Dev.
(2007) Noncoding RNA genes
Curr. Opin. Genet. Dev.
(1999)- et al.
The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus
Cell
(1992) - et al.
A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response
Cell
(2010) - et al.
Coding vs non-coding: translatability of short ORFs found in putative non-coding transcripts
Biochimie
(2011) The can and can't dos of p53 RNA
Biochimie
(2011)- et al.
Steroid receptor RNA activator bi-faceted genetic system: heads or Tails?
Biochimie
(2011) - et al.
The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation
Mol. Cell
(2010) - et al.
3′ end processing of a long nuclear-retained noncoding RNA yields a tRNA-like cytoplasmic RNA
Cell
(2008) - et al.
Emerging roles for natural microRNA sponges
Curr. Biol.
(2010)
Phosphatase and tensin homolog (PTEN) pseudogene expression in endometrial cancer: a conserved regulatory mechanism important in tumorigenesis?
Gynecol. Oncol.
LincRNA-p21 suppresses target mRNA translation
Mol. Cell
Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription
Nature
Long noncoding RNAs and human disease
Trends Cell Biol.
Deletion of PTENP1 pseudogene in human melanoma
J. Invest. Dermatol.
A long ncRNA links copy number variation to a polycomb/trithorax epigenetic switch in FSHD muscular dystrophy
Cell
A long noncoding RNA activated by TGF-beta promotes the invasion-metastasis cascade in hepatocellular carcinoma
Cancer Cell
Natural antisense transcripts of hypoxia-inducible factor 1alpha are detected in different normal and tumour human tissues
Gene
Activation of negative regulators of the hypoxia-inducible factor (HIF) pathway in human end-stage heart failure
Biochem. Biophys. Res. Commun.
Elevation of highly up-regulated in liver cancer (HULC) by hepatitis B virus X protein promotes hepatoma cell proliferation via down-regulating p18
J. Biol. Chem.
Hallmarks of cancer: the next generation
Cell
Concerns about targeting cancer stem cell for cancer therapy
Med. Hypotheses
Genome-wide mapping and characterization of notch-regulated long noncoding RNAs in acute leukemia
Cell
Cancer stem cells and metastasis
Semin. Cancer Biol.
The long noncoding MALAT-1 RNA indicates a poor prognosis in non-small cell lung cancer and induces migration and tumor growth
J. Thorac. Oncol.
General nature of the genetic code for proteins
Nature
Annotating noncoding RNA genes
Annu. Rev. Genomics Hum. Genet.
Non-coding RNAs as regulators of embryogenesis
Nat. Rev. Genet.
Developmental control of allelic methylation in the imprinted mouse Igf2 and H19 genes
Development
An integrated encyclopedia of DNA elements in the human genome
Nature
The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression
Genome Res.
Long non-coding RNAs: insights into functions
Nat. Rev. Genet.
Long intergenic noncoding RNAs: new links in cancer progression
Cancer Res.
LNCipedia: a database for annotated human lncRNA transcript sequences and structures
Nucleic Acids Res.
Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals
Nature
Emerging roles of non-coding RNAs in brain evolution, development, plasticity and disease
Nat. Rev. Neurosci.
Genome-wide analysis reveals distinct patterns of epigenetic features in long non-coding RNA loci
Nucleic Acids Res.
Genome-wide evidence for an essential role of the human Staf/ZNF143 transcription factor in bidirectional transcription
Nucleic Acids Res.
Conserved introns reveal novel transcripts in Drosophila melanogaster
Genome Res.
Genome regulation by long noncoding RNAs
Annu. Rev. Biochem.
Long noncoding RNA in genome regulation: prospects and mechanisms
RNA Biol.
ADAR-mediated RNA editing in non-coding RNA sequences
Sci China Life Sci
A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial–mesenchymal transition
Genes Dev.
Integrative transcriptome analysis suggest processing of a subset of long non-coding RNAs to small RNAs
Biol. Direct
Regulation of H19 and its encoded microRNA-675 in osteoarthritis and under anabolic and catabolic in vitro conditions
J. Mol. Med. (Berl)
miR-31 and its host gene lncRNA LOC554202 are regulated by promoter hypermethylation in triple-negative breast cancer
Mol. Cancer
miRcode: a map of putative microRNA target sites in the long non-coding transcriptome
Bioinformatics
CREB up-regulates long non-coding RNA, HULC expression through interaction with microRNA-372 in liver cancer
Nucleic Acids Res.
A coding-independent function of gene and pseudogene mRNAs regulates tumour biology
Nature
miRNA-dependent gene silencing involving Ago2-mediated cleavage of a circular antisense RNA
EMBO J.
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These authors contributed equally to this work.