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Page 2 of 23 Parsons et al. J Cancer Metastasis Treat 2018;4:19 I http://dx.doi.org/10.20517/2394-4722.2018.11

INTRODUCTION
Metastasis is the leading cause of cancer-related deaths world-wide . Understanding the biological processes
[1]
that control the initiation and progression of metastasis is crucial in reducing tumor-related deaths
associated with carcinomas . Metastasis consists of the following phases: (1) escape of cells from the
[2,3]
[4]
primary tumor and invasion into the surrounding mesenchyme ; (2) intravasation into adjacent vasculature
and the lymphatic system ; (3) upregulation of cell survival mechanisms via resistance to apoptosis and
[5]
anoikis ; (4) extravasation from the vasculature and subsequent infiltration into the parenchyma of a
[6]
distant organ site ; and (5) the ability to undergo micro-metastatic colonization, and survival within a
[7]
new tissue microenvironment . The epithelial to mesenchymal transition (EMT) is a key developmental
[8,9]
regulatory program describing the initiating processes of metastasis, and involves a linear series of events
including tightly organized epithelial cells undergoing a loss of cellular polarity, and the ability for cells to
survive under anchorage-independent conditions, both of which supports the propagation of migratory cells
[10]
able to invade distant organ sites . EMT essentially reactivates the embryonic morphogenesis and wound
healing programs normally kept inactive within differentiated epithelial cells [11-13] . Therefore, investigating
the series of cellular reprogramming events required for differentiated epithelial cells to acquire an invasive
mesenchymal phenotype will aid in the development of therapeutics that specifically target metastatic cells.

While many zinc finger transcription factors (TFs) have been identified as regulators of EMT, including
zinc-finger enhancer binding 1 (ZEB1), Snail, and Slug, little is known regarding the initiating steps that
drive the transition of polar cells of an epithelial origin towards those with mesenchymal characteristics [14,15] .
Furthermore, given invasive metastatic cells hone to various tissue sites depending upon the tissue of
origin from which the primary tumor derives (i.e., the “seed and soil hypothesis”), one can hypothesize
that ubiquitously expressed TFs such as Snail cannot be the sole contributor of a cell-context dependent
regulatory process such as metastasis [16,17] . In fact, in a recent survey of the human genomic landscape,
there is striking evidence that noncoding RNAs (ncRNAs) play an important and diverse role in regulating
developmental transitions. Moreover, ncRNAs control the spatial and temporal tuning of cellular signaling
pathways important for the proper execution of functional phenotypes such as enhanced cellular proliferation,
migration, and/or survival [18-26] . Furthermore, in cancers that are dependent upon changes in the abundance
and bioavailability of steroid hormones such as 17β-estradiol, ncRNAs have been identified to play a key role
in the abrogating hormone-mediated metastasis [19,27-33] .

Therefore, ncRNAs are considered important epigenetic regulators of the transcriptome that modulate
context-specific processes involved in promoting a metastatic phenotype. One class of ncRNA includes
microRNAs (miRNAs), which are short 22-nucleotide (nt) ncRNAs that undergo biochemical processing
from a longer primary miRNA (pri-miRNA) transcript via a series of interactions with RNase-III type
proteins that include DROSHA and DICER. miRNAs operate via a distinct mechanism of action that relies
upon imperfect complementarity or Watson-Crick base-pairing between a miRNA and the 3’ untranslated
region (3’ UTR) of a target messenger RNA (mRNA) . miRNAs therefore serve as guides that recruit RNA
[34]
binding proteins (RBPs) such as AGO2 to specific mRNA targets resulting in reduced gene expression either
via translational inhibition or via RNA degradation [25,35-37] .

Given this imperfect complementarity, miRNAs function as pleiotropic regulators of cell signaling pathways
critically important in maintaining proper tissue development, as well as inhibiting the initiation and
progression of tumorigenic cascades . Given miRNAs operate by fine-tuning gene expression, and themselves
[38]
function as either oncogenes or tumor suppressors when dysregulated, these ncRNAs subsequently present
as potential targets for therapeutic development across a wide number of genetic disorders. miRNAs also
modulate the expression of genes considered initiators of EMT, as well as mediators of downstream metastatic
processes such as micro-metastatic colonization, anoikis, and interactions within the surrounding tumor
microenvironment. For instance, miR-10b is a miRNA expressed at high levels in metastatic breast cancer