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Page 8 of 23 Parsons et al. J Cancer Metastasis Treat 2018;4:19 I http://dx.doi.org/10.20517/2394-4722.2018.11

and HMGA2 oncogenes in epithelial tumors, altering the metastatic potential of these cells [87-90] . However,
let-7 also binds to well established oncogenic lncRNAs such as H19 and HOTAIR , which promotes post-
[91]
transcriptional repression of gene targets via AGO2-mediated lncRNA degradation. let-7 also reduces
lncRNA levels through a separate mechanism of RNA decay by recruiting HuR binding proteins to AU-rich
regions of the targeted ncRNA transcript. Other examples of lncRNAs that are regulated via the ceRNA
hypothesis include interactions with lncRNA sponges. For instance, HULC and lncRNA-ATB can bind miR-
372 and miR-200 respectively, but does not result in the degradation of the lncRNA [92,93] . Rather, miR-372
binding to HULC precludes miR-372 binding to bona fide mRNA targets such as LATS2 . This sponging
[94]
phenotype of removing an inhibitor of LATS2 expression is relevant as LATS2 itself is a tumor suppressor.
Therefore, HULC along with a number of other lncRNAs function as sponges or decoys that operate together
to modulate the ncRNA network important for the manifestation of a particular cellular phenotype.

lncRNAs modulate cell signaling pathways
In bacteria and yeast systems researchers observed that lncRNAs associate with protein modules localized
to the cellular membrane , indicating lncRNAs are not only present within the cytoplasm, but also operate
[95]
within functionally discrete cytoplasmic compartments. The result of these lncRNA-chaperone protein
interactions is the modulation of cell signaling networks through the activation or inhibition of a particular
receptor tyrosine kinase (RTK) via the recruitment of cytoplasmic kinases or phosphatases. For instance,
in eukaryotic systems, Uchl1 codes for an important enzyme specifically expressed within dopaminergic
neurons, and the activity of this protein is regulated by an antisense SINEB2 element as well as an
antisense transcript AS-Uchl1 [96,97] . Under conditions of metabolic stress, such rapamycin treatment, AS-
Uchl1 subcellular localization transitions from being primarily nuclear in abundance towards cytoplasmic
enrichment, with discrete foci detectable by FISH at active polysomes due to the 5’ cap-independent
translation of Uch11.

In another scenario, lnc-DC is a lncRNA expressed within dendritic cells, and is a crucial component for
the activation of STAT3 signaling. This modulation of STAT3 activity occurs because lnc-DC binds to SHP1-
containing protein foci, preventing SHP1-STAT3 interactions, and, in turn, allowing for phosphorylation of
STAT3 at residue tyrosine-705 by a number of kinases . This implies that lncRNAs function as scaffolds
[98]
that recruit cytoplasmic enzymes (i.e., ubiquitinases, or kinases) essential in mediating post-translational
modifications of cytoplasmic proteins. These observations also raise questions as to whether lncRNAs can
recruit adaptor proteins such as GRB2 to the vicinity of the carboxy-termini of membrane-bound receptors
containing SH2 domains, which are responsible for the direct modulation of RTK-mediated cell signaling
cascades. These observations also support an earlier hypothesis from studies on RNA viruses, concerning
RNA-lipid interactions, specifically those with charged moieties including phosphatidylcholine (PC) and
phosphatidylserine (PS), are crucial in supporting life [99-102] . Further work is warranted to elucidate the
complexities of these lncRNAs that operate as trans regulators of cell signaling pathways.

ROLE FOR NCRNAS IN CANCER METASTASIS
The role of ncRNAs in the progression of the metastatic cascade has gained interest over the past decade.
Small nucleolar RNAs (snoRNAs) for instance regulate the presence of ribosomal RNA (rRNA) modifications
important in modulating a number of cellular phenotypes. snoRNAs are essential modulators of pre-rRNA
processing through formation of a 10-21 nt RNA duplex around a specific base-pair modification [103-105] .
These modifications direct the snoRNA complex to the location of enzymatic cleavage of A-sites on the pre-
rRNA molecule resulting in liberation from the rRNA processing complex. snoRNAs are also important in
the regulation of the spliceosome complex and the splicing of introns across a number of RNA molecules,
including mRNAs, lncRNAs, and rRNAs [106,107] . snoRNAs can also regulate mRNA molecules at single nt
resolution, mostly via methylation of adenosines (i.e., m6A) that alter the post-transcriptional processing of
those modified mRNAs, or via 2’-O-ribose methylation of the spliceosomal machinery. Finally, snoRNAs are