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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 13 of 23

β-catenin, which in turn resulted in reduced CCND1 and MYC protein expression [162-168] . Moreover, the
phenotypes observed under CCAT2 knockdown conditions operated synergistically with small molecule
WNT inhibitor, FH-535. These studies indicate CCAT2 imparts a specific regulatory function through the
augmentation of the WNT signaling pathway, and as such, contributes to a pro-metastatic phenotype.

Myocardial infarction associated transcript
The lncRNA myocardial infarction associated transcript (MIAT) has been linked to several chronic
disorders including myocardial infarction [169,170] , paranoid schizophrenia , and neuroendocrine-derived
[171]
prostate cancers . MIAT interacts with a number of epigenetic modifiers in neuronal crest cells including
[110]
PRC1/2 and ZEB1 that when altered results in the modified migratory capacities of these cell lines . MIAT
[172]
is also disrupted in a number of cancer cell lines, and is expressed at significantly lower levels in grade
I-II breast tumors, as compared to those considered high grade III-IV tumors . MIAT also modulates
[110]
the invasive capacities of breast cancer cells by mediating the ncRNA interaction networks between ZEB1
and certain miRNAs, such as miR-150 and miR-29 . For instance, knockdown of MIAT promotes the
[173]
expression of miR-150, yet also results in the reduction of miR-29 levels. This results in breast tumor cell
lines transitioning from a pro-proliferative state towards a more quiescent yet migratory phenotype [72,174,175] .
There are two mechanisms by which MIAT could alter these miRNA interaction networks. The first is that
MIAT functions as a ceRNA and operates as a sponge for miR-150, reducing the bioavailability of miR-150
to interact with cognate mRNA transcripts such as ZEB1. The second is that MIAT operates as a chaperone
or scaffold that recruits co-repressor complexes to the promoter of the MIR150 host gene, subsequently
reducing the transcriptional output of miR-150. While both scenarios may not be mutually exclusive from one
another, these regulatory interactions reinforce the notion that EMT is a highly controlled cellular program
responsible for modulating the expression of E-cadherin, which is initiated by several key transcriptional
repressors including ZEB1 [176,177] . Interestingly, the resulting consequence of the MIAT-miR-150 interaction
is the increased expression of ZEB1 and, in turn, a pro-metastatic phenotype, through the transcriptional
upregulation of the MIR29 host gene. miR-29 promotes the invasive capabilities of cells by diverting the
energy demand required for cellular proliferation and redirecting those energies towards signaling pathways
that encourage motility and invasion [178,179] . This occurs in part by modulating the expression of cell-cycle
checkpoint genes such as CDKN2A. Therefore, MIAT represents a characteristic example of how lncRNAs
can modulate the activity of RNA-RNA interactions by controlling the bioavailability of other ncRNAs, in
turn, reprograming cellular signaling cascades to support a pro-metastatic phenotype.

BMP/OP-responsive gene
Recently, the lncRNA BMP/OP-responsive gene (BORG) was identified to play a vital role in augmenting
proliferation and survival cues within breast cancer cells [71,180] . Specifically, BORG interacts with the
TRIM28 TF, which modulates the transcriptional co-repression of Cdkn1a and Gadd45a [181,182] . The presence
of this BORG-TRIM28 binding complex is also linked with shorter tumor latency within breast cancer
patients and correlates with a faster outgrowth of cancer cells in 3D culture systems. TRIM28 can also
function as a transcriptional activator or repressor depending upon the chromatin architecture or extent of
heterochromatization within the nucleus. BORG localizes predominantly to the nucleus and has a unique
function as it reinforces the repressive actions associated with TRIM28. As an example, repression of BORG
in metastatic D2.A1 breast cancer cells prevents migratory outgrowths within 3D matrigel culture systems,
as well as the abundance of micro-metastatic colonies in lung tissue utilizing an invasive breast cancer
transplant model . Furthermore, in aggressive metastatic breast cancer the expression of BORG is higher
[180]
as compared to samples derived from non-malignant mammary tissues. Therefore, BORG clearly modulates
the invasive capacities of breast cancer cells.

While RNA immunoprecipitation (RIP) experiments indicate that TRIM28 in fact requires BORG for
binding to specific gene promoter regions, such as those neighboring Cdkn1a and Gadd45a , it is still
[180]