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samples, and the use of anti-miRNA oligonucleotides significantly reduces metastatic lesions in mouse
models [39,40] . Additionally, miRNAs such as miR-148a regulate the levels of E-cadherin and subsequently
the progression of EMT via the modulation of DNMT1 activity , while the miR-17 family of miRNAs
[41]
controls metastatic phenotypes in lung cancer via dampening the expression of transforming growth factor
(TGF)-β . Comprehensive reviews of miRNA in cancer are discussed in greater detail elsewhere [43,44] .
[42]

lncRNAs are a newly discovered class of ncRNA important in dampening stochastic gene expression by
modulating the epigenetic landscape of the genome. lncRNAs are a divergent class of ncRNA molecule greater
than 200 nt in length that lack protein-coding capacity, yet control a diverse array of biological processes
via the recruitment of chromatin modifiers to specific genomic loci or by modulating post-transcriptional
processes [45,46] . Currently there are over 118,000 high confidence lncRNA transcripts identified in Homo
sapiens (http://www.lncipedia.org), many of which have no ascribed biological function. However, a number
of studies have begun elucidating particular ncRNAs dysregulated across multiple cancer types [19,47-49] . The
challenge in studying lncRNAs is their relatively low abundance and reduced conservation across species as
compared to protein coding transcripts and other ncRNAs such as miRNAs . This led many to believe that
[50]
lncRNAs derive from leaky transcriptional processes and, therefore, have limited functionality in regulating
cellular processes. However, there is considerable evidence that lncRNAs regulate the physiological pathways
required for the initiation and maintenance of the metastatic process.

Broadly speaking, the diminished level of a lncRNA within a cell, results in the reduced bioavailability of a
particular enzymatic substrate important in modulating chromatin structure as well as the transcriptional
activity of neighboring protein coding genes. This occurs via a chaperone mechanism whereby a lncRNA
brings into proximity RBPs, as well as components of the transcriptional machinery including RNA polII,
to discrete genetic loci facilitating proper TF binding [35,45,51-58] . Therefore, the abundance of any particular
lncRNA is important in providing the specificity necessary to promote certain phenotypic outcomes required
during the metastatic cascade [59,60] . While investigators have identified specific roles for lncRNAs that control
a number of cellular functions including differentiation, invasion, and metastasis, this review focuses on the
role of lncRNAs within the metastatic process [Table 1].

LNCRNA NOMENCLATURE
lncRNAs are a heterogeneous class of ncRNA transcribed from a number of regions within the genome,
and in varying orientations that flank neighboring protein coding genes, promoting a diverse combination
of functional phenotypes. The nomenclature of lncRNAs is still controversial; however, a concerted effort
has been made to group lncRNAs into functional categories based on the genomic localization of these
transcripts, as well as the regulatory functions they confer [Figure 1]. For instance, promoter-associated
lncRNAs (pa-lncRNAs) are transcribed in an antisense orientation from a shared promoter of a neighboring
protein coding gene . A majority of pa-lncRNAs operate in cis and recruit chaperone proteins that modulate
[61]
the transcription of the neighboring protein coding gene, though this is not always the case [62,63] . For instance,
a pa-lncRNA was found to be transcribed from the cyclin D1 promoter and is important in mediating the
inhibitory activity of certain histone acetyltransferases .
[64]
Enhancer-associated lncRNAs (ea-lncRNAs) are similar to pa-lncRNAs, yet they originate from active
enhancer regions within the genome that promote cis-activation of transcription via DNA looping at
the proximal promoters of nearby protein coding genes . ea-lncRNAs are also released from the site of
[65]
transcription, and modulate the activity of distal gene promoters in trans through the recruitment of co-
activators such as, p300/cAMP response element-binding protein (CREBP), as well as, demethylases such as
lysine-specific demethylase 1 (LSD1) [66,67] . As an example, Braveheart (Bvht) is a lncRNA transcribed from
an enhancer region marked by H3K27Ac, associates with cardiac specific transcriptional enhancers, and