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Parsons et al. J Cancer Metastasis Treat 2018;4:19 I http://dx.doi.org/10.20517/2394-4722.2018.11 Page 5 of 23
Table 1. lncRNAs associated with and tumorigenesis and EMT pathways
lncRNA Cancer type Expression in cancer References Role in metastasis
MALAT1 Lung Upregulated [190]
Bladder Upregulated [192] Suppression of E-cadherin [191]
Breast Upregulated [193]
Pancreatic Upregulated [194]
MEG3 Meningioma Downregulated [195]
Lung Downregulated [198] Regulation of autophagy [196] and DNA repair [197]
Gastric Downregulated [199]
HOTAIR Liver Upregulated [200]
Breast Upregulated [203] Reprogramming of chromatin state [201,202]
Pancreatic Upregulated [204]
GAS5 Liver Downregulated [205]
Gastric Downregulated [207] Controls invasion by control of miRNAs [205,206]
Breast Downregulated [208]
H19 Liver Upregulated [209]
Pancreatic Upregulated [137,212] Chromatin remodeling [210] and TGF-β regulation [211]
Gastric Upregulated [213]
HULC Liver Upregulated [147]
Gastric Upregulated [148] Regulates tumor microenvironment interactions [214]
Breast Upregulated [92,146]
SPRY4-IT1 Melanoma Upregulated [139]
Lung Upregulated [215] Proliferation and invasion via regulation of EZH2 [143]
SCC Upregulated [142]
HIF1A-AS2 is also important in regulating hypoxic responses in A549 lung cancer cells . In fact, hypoxia
[72]
induces HIF1A-AS2 expression, which in turn binds and represses HIF1α levels under hypoxic conditions
presumably through a process of RNA-mediated decay.
Gene body associated lncRNAs (gba-lncRNAs) differ from NATs, and originate instead from the sense
strand of a respective protein coding gene loci [73-75] . An example of a gba-lncRNA is the pseudogene
transcribed from the CCAAT/enhancer binding protein alpha (C/EBPα) locus, termed ecCEBPA, which
utilizes a separate open reading frame (ORF) and transcriptional start site (TSS) neighboring the C/EBPα
gene locus . ecCEBPA interacts with DNMT1, resulting in decreased methylation of the CEBPA gene.
[76]
Mutagenesis studies further indicated that ecCEBPA contains hairpin structures that favor DNMT1 binding
suggesting lncRNAs are important in modulating not only transcriptome wide DNA methylation, but are
also present at sites of active transcription. Other gba-lncRNAs can operate as sponges for ncRNAs, thereby
modulating the bioavailability of mRNA transcripts within a cell [73,74] . This competitive endogenous RNA
(ceRNA) code or hypothesis is discussed in greater detail later in the review.
Finally, long intergenic noncoding RNAs (lincRNA) span extensive regions of the genome and are found
within intronic regions of a coding gene, rather than as discrete genetic elements . Examples include
[71]
HOTAIR and MALAT1 [Figure 1]. One of the first lincRNAs discovered, X inactive specific transcript (XIST),
produces an approximately 20 kilobase (kb) noncoding lincRNA and functions to silence the expression
of genes derived from the inactive X chromosome (Xi) through recruitment of the polycomb repressive
complex (PRC1/2) . The precise mechanism by which XIST recruits PRC1/2 to the X-chromosome is still
[77]
unclear, as X-inactivation requires an evenly distributed presence of PRC1/2 across the Xi so as to ensure
the proper silencing of both coding and noncoding transcripts [Figure 2B]. Some have indicated that the
silencing of Xi is accompanied by phosphorylation events on p53, indicating XIST cooperates with the p53
DNA-repair machinery during X-inactivation . Given other ncRNAs such as miR-34 are known regulators
[78]
of TP53 expression in cancer cell lines as well as during development , this raises the notion that lincRNAs
[79]
cooperate with ncRNAs to carry out specific cellular programs. XIST also mediates epigenetic interactions
between PRC1/2 and specific gene loci via interactions with chromatin modifiers such as SHARP, SAF-A,