Review
LncRNA: A link between RNA and cancer

https://doi.org/10.1016/j.bbagrm.2014.08.012Get rights and content

Highlights

  • LncRNAs function as a platform for the complicated interaction with miRNA, mRNA, protein or their combination.

  • LncRNAs have emerged as an essential regulator in almost every aspect of biology.

  • Misexpression of lncRNAs confers the cancer cell capacities for tumor initiation, growth, and metastasis.

  • LncRNAs serve as a promising target for cancer diagnosis and therapy.

Abstract

Unraveling the gene expression networks governing cancer initiation and development is essential while remains largely uncompleted. With the innovations in RNA-seq technologies and computational biology, long noncoding RNAs (lncRNAs) are being identified and characterized at a rapid pace. Recent findings reveal that lncRNAs are implicated in serial steps of cancer development. These lncRNAs interact with DNA, RNA, protein molecules and/or their combinations, acting as an essential regulator in chromatin organization, and transcriptional and post-transcriptional regulation. Their misexpression confers the cancer cell capacities for tumor initiation, growth, and metastasis. The review here will emphasize their aberrant expression and function in cancer, and the roles in cancer diagnosis and therapy will be also discussed.

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)

  • Y.J. Ioffe et al.

    Phosphatase and tensin homolog (PTEN) pseudogene expression in endometrial cancer: a conserved regulatory mechanism important in tumorigenesis?

    Gynecol. Oncol.

    (2012)
  • J.H. Yoon et al.

    LincRNA-p21 suppresses target mRNA translation

    Mol. Cell

    (2012)
  • X. Wang et al.

    Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription

    Nature

    (2008)
  • O. Wapinski et al.

    Long noncoding RNAs and human disease

    Trends Cell Biol.

    (2011)
  • L. Poliseno et al.

    Deletion of PTENP1 pseudogene in human melanoma

    J. Invest. Dermatol.

    (2011)
  • D.S. Cabianca et al.

    A long ncRNA links copy number variation to a polycomb/trithorax epigenetic switch in FSHD muscular dystrophy

    Cell

    (2012)
  • J.H. Yuan et al.

    A long noncoding RNA activated by TGF-beta promotes the invasion-metastasis cascade in hepatocellular carcinoma

    Cancer Cell

    (2014)
  • F. Rossignol et al.

    Natural antisense transcripts of hypoxia-inducible factor 1alpha are detected in different normal and tumour human tissues

    Gene

    (2002)
  • O. Zolk et al.

    Activation of negative regulators of the hypoxia-inducible factor (HIF) pathway in human end-stage heart failure

    Biochem. Biophys. Res. Commun.

    (2008)
  • Y. Du et al.

    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.

    (2012)
  • D. Hanahan et al.

    Hallmarks of cancer: the next generation

    Cell

    (2011)
  • G. Yang et al.

    Concerns about targeting cancer stem cell for cancer therapy

    Med. Hypotheses

    (2011)
  • T. Trimarchi et al.

    Genome-wide mapping and characterization of notch-regulated long noncoding RNAs in acute leukemia

    Cell

    (2014)
  • K. Sampieri et al.

    Cancer stem cells and metastasis

    Semin. Cancer Biol.

    (2012)
  • L.H. Schmidt et al.

    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.

    (2011)
  • F.H. Crick et al.

    General nature of the genetic code for proteins

    Nature

    (1961)
  • S. Griffiths-Jones

    Annotating noncoding RNA genes

    Annu. Rev. Genomics Hum. Genet.

    (2007)
  • A. Pauli et al.

    Non-coding RNAs as regulators of embryogenesis

    Nat. Rev. Genet.

    (2011)
  • R. Feil et al.

    Developmental control of allelic methylation in the imprinted mouse Igf2 and H19 genes

    Development

    (1994)
  • B.E. Bernstein et al.

    An integrated encyclopedia of DNA elements in the human genome

    Nature

    (2012)
  • T. Derrien et al.

    The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression

    Genome Res.

    (2012)
  • T.R. Mercer et al.

    Long non-coding RNAs: insights into functions

    Nat. Rev. Genet.

    (2009)
  • M.C. Tsai et al.

    Long intergenic noncoding RNAs: new links in cancer progression

    Cancer Res.

    (2011)
  • P.J. Volders et al.

    LNCipedia: a database for annotated human lncRNA transcript sequences and structures

    Nucleic Acids Res.

    (2013)
  • M. Guttman et al.

    Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals

    Nature

    (2009)
  • I.A. Qureshi et al.

    Emerging roles of non-coding RNAs in brain evolution, development, plasticity and disease

    Nat. Rev. Neurosci.

    (2012)
  • S. Sati et al.

    Genome-wide analysis reveals distinct patterns of epigenetic features in long non-coding RNA loci

    Nucleic Acids Res.

    (2012)
  • Y.N. Anno et al.

    Genome-wide evidence for an essential role of the human Staf/ZNF143 transcription factor in bidirectional transcription

    Nucleic Acids Res.

    (2011)
  • M. Hiller et al.

    Conserved introns reveal novel transcripts in Drosophila melanogaster

    Genome Res.

    (2009)
  • J.L. Rinn et al.

    Genome regulation by long noncoding RNAs

    Annu. Rev. Biochem.

    (2012)
  • T. Hung et al.

    Long noncoding RNA in genome regulation: prospects and mechanisms

    RNA Biol.

    (2010)
  • Y. Yang et al.

    ADAR-mediated RNA editing in non-coding RNA sequences

    Sci China Life Sci

    (2013)
  • M. Beltran et al.

    A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial–mesenchymal transition

    Genes Dev.

    (2008)
  • S. Jalali et al.

    Integrative transcriptome analysis suggest processing of a subset of long non-coding RNAs to small RNAs

    Biol. Direct

    (2012)
  • E. Steck et al.

    Regulation of H19 and its encoded microRNA-675 in osteoarthritis and under anabolic and catabolic in vitro conditions

    J. Mol. Med. (Berl)

    (2012)
  • K. Augoff et al.

    miR-31 and its host gene lncRNA LOC554202 are regulated by promoter hypermethylation in triple-negative breast cancer

    Mol. Cancer

    (2012)
  • A. Jeggari et al.

    miRcode: a map of putative microRNA target sites in the long non-coding transcriptome

    Bioinformatics

    (2012)
  • J. Wang et al.

    CREB up-regulates long non-coding RNA, HULC expression through interaction with microRNA-372 in liver cancer

    Nucleic Acids Res.

    (2010)
  • L. Poliseno et al.

    A coding-independent function of gene and pseudogene mRNAs regulates tumour biology

    Nature

    (2010)
  • T.B. Hansen et al.

    miRNA-dependent gene silencing involving Ago2-mediated cleavage of a circular antisense RNA

    EMBO J.

    (2011)
  • Cited by (0)

    1

    These authors contributed equally to this work.

    View full text