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of those genes. [12] However, lincRNA-p21 interacts with was also observed between Kras and its pseudogene
hnRNP-K and helps enrichment of hnRNP-K into these KRAS1P. KRAS1P is amplified in most of cancers with
promoters, resulting in transcription suppression. On the activated Kras, indicating a positive correlation between
[13]
other hand, p53 enhances transcription of lincRNA-p21, them. Although how KRAS1P regulates KRAS level is not
thus forming an auto-regulatory feedback loop. well-understood, it may act as a sponge for miRNAs that
bind to the 3’-UTR of Kras and prevents degradation of Kras
LNCRNA AS A PROGENITOR OF SMALL transcript. The lncRNA decoy function is not limited to
[19]
RNAS, REGULATING THEIR FUNCTIONS miRNAs, and it can also be applied to DNA. For instance,
Gas5, which is enriched in growth-arrested cells, inhibits
[20]
Although there is still no concrete evidence yet, lncRNAs the function of glucocorticoid receptor (GR) by competing
may be post-transcriptionally processed into the small with glucocorticoid response element (GRE) to bind GR.
RNAs. For instance, the computational analysis indicated GR is a transcription factor and is activated by ligand and
that exons of lncRNAs are highly enriched with small subsequently the activated GR binds to GRE to initiate
RNAs. In fact, snoRNAs are enriched 6-fold higher in transcription of downstream genes. A part of Gas5 sequence
their exons than any other genomic loci. Similarly, many is capable of forming 6 hairpin structures; among them,
[14]
miRNAs are derived from transcripts which are capped and hairpin structure 5 has two GRE-like structures that mimic
polyadenylated including lncRNAs. About 20% miRNAs GRE. Therefore, GR could bind Gas5 instead of GRE,
are overlapped with either introns or exons of lncRNAs. and as a result, this interaction hinders the GR-mediated
[15]
LncRNA H19 is one such prominent example which serves transcription activity. [21]
as the precursor of miRNA. The pri- and pre-miR-675
resides in H19 and expression of miR-675 coincides with LNCRNAS AS A SCAFFOLDING AND
H19 in murine embryo. However, miR-675 is not expressed STRUCTURAL SUPPORT
in NIH3T3 cells that lack H19 expression. The digestion
of 32P-labeled H19 clone with Drosha: DGCR8 (enzyme Physical association between cellular entities is critically
for miRNA biogenesis) releases 57 nucleotide long pre- important for coordination of a variety of cellular functions.
miRNA 675, indicating that H19 is the parental transcript It is well-known that specific binding between two different
of miR-675. [16] cellular components can control the reprogramming of
cellular signaling, leading to alternations of cell phenotype
LncRNAs not only serve as the precursor for the small or function. Apparently, proteins can serve such function
RNAs but also regulate the expression and the function of as a scaffolding and structural support. Recent studies
[22]
miRNAs. The lncRNAs provide putative binding sites for suggest that lncRNAs can also have a similar function
miRNAs. Such interactions alter the expression and the because they can interact with different proteins, through
function of mature miRNAs. For example, loc285194 is a which lncRNAs provide a platform for the assembly of
tumor suppressor in colon cancer and it carries two binding various proteins. Such interactions may affect protein
sites for oncogenic miR-211. This interaction does not affect localization, protein function, transcriptional activity, gene
the pri- and pre-miR-211 level but alters the mature miR- splicing, etc. Linc-ROR is lncRNA as a regulator of induced
211. Similarly, growth arrest-specific 5 (Gas5) regulates pluripotent cell reprogramming. Of interest, linc-ROR
[23]
[17]
the level of miR-21 through their interaction. Apparently, plays an important role in repression of p53 translation by
Gas5 does not affect the pre- and pri-miR-21. Moreover, interaction with phosphorylated hnRNP I in the cytoplasm.
both miR-21 and Gas5 are found in RNA-induced silencing The physical association between linc-ROR and hnRNP I
complex (RISC), suggesting that Gas5 regulates miR-21 controls p53 translation and deletion of hnRNP I binding
through RNA interference (RNAi) mechanism. [18] motif in linc-ROR abolishes its repression capability. The
[24]
scaffolding function of lncRNAs is also essential for the
LNCRNAS AS A DECOY formation of special architect-like paraspeckles, a nuclear
body structure that appears during interphase of cell cycle.
A pseudogene is a class of lncRNAs, derived from mutations Paraspeckles are primarily composed of proteins such as
in protein-coding genes. They usually have similar paraspeckle protein (PSP1, PSP2) and p54/nrb. Although
[25]
sequences to their parental gene with few mismatches. the function of paraspeckles is still not clear, components
This resemblance in structure could entice different cellular within paraspeckles are known to play an important role for
entities as lncRNAs rather than mRNAs, impacting the transcription and alternative splicing. [26,27] Since paraspeckles
cellular function. For example, PTENP1 is a mutated form do not have any membrane structure, lncRNAs within the
of PTEN and their sequences differ by only 18 mismatches. paraspeckle may help to establish this compartment.
[28]
PTEN carries a number of different sites for miRNA in NEAT1 is one of the lncRNAs that interact with PSP1 and
its untranslated region (3’-UTR). Although PTENP1 is 1 together, they may help to form paraspeckles. Importantly,
kb shorter in the 3’-UTR than PTEN, most of the miRNA the number of paraspeckles increases in vivo and in vitro with
binding sites are conserved. This can trap many miRNAs to the increase in NEAT 1 expression and deletion of NEAT1
PTENP1 to compete with PTEN. A similar relationship eliminates the paraspeckles, suggesting an important role of
[19]

Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ Issue 1 ¦ January 15, 2016 ¦ 3