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Page 10 of 23 Parsons et al. J Cancer Metastasis Treat 2018;4:19 I http://dx.doi.org/10.20517/2394-4722.2018.11

these papers discuss how particular lncRNAs regulate the biochemical steps crucial for the initiation and
maintenance of metastatic dissemination. These new lncRNAs are intriguing entities to study, as they have
putative tumorigenic activity across a number of epithelial tumors, and are expressed at levels sufficient
enough for investigators to perform both gain- and loss-of-function studies, and to assess the phenotypes
that result upon lncRNA dysregulation.

Elucidating the role of these lncRNAs could further illuminate our understanding of the regulatory processes
involved in the initiation of cellular depolarization and motility, as well as the crucial genetic factors required
for metastatic dissemination. Below, we highlight examples of a few lncRNAs that regulate important cellular
activities in epithelial tumors, which could be utilized for the development of new therapeutics for patients
with metastatic disease.

H19
H19 is a 2.3-kb oncofetal lncRNA gene derived from the IGF2 locus important in regulating cellular
differentiation programs during development, including maternal imprinting . While H19 is expressed
[120]
from only one parental allele, robust levels of H19 are present during embryonic development, which is
rapidly downregulated postnatally [121-125] . Improper H19 gene dosage compensation due to the lack of
maternal imprinting results in embryonic lethality in mice, associates with certain clinical manifestations
of those with Beckwith-Wiedemann syndrome, and correlates with an increased risk of developing Wilms
tumor of the kidney [126-129] . H19 is also highly expressed in a number of tumors, and supports metastases
by antagonizing ncRNAs and epigenetic regulators, such as chromatin modifiers crucial in maintaining
epithelial polarity . A recent study indicated that a single nucleotide polymorphism (SNP), rs2107425
[130]
located within an intron of the H19 gene, was associated with reduced metastatic free survival. This SNP
does not affect the abundance of H19 in breast cancer patients, as compared to those not harboring the
rs2107425 variant. Instead, this SNP alters the activity of H19 either by preventing binding to a cognate
ncRNA or RBP responsible for modulating metastatic processes, or by promoting an alternative splicing
event resulting in the modulation of the ceRNA network .
[131]

H19 also has a direct role in regulating the cellular processes of invasion and angiogenesis crucial for the
progression of metastatic disease. For instance, H19 associates with the TF enhancer of zeste homolog
2 (EZH2) in turn downregulating the expression of gatekeeper genes such as E-cadherin and adenoma
polyposis coli (APC) [131,132] . H19 also supports constitutive WNT signaling by inhibiting the activity the
WNT-antagonist Nkd1. Given Nkd1 inhibits WNT activity, it is plausible H19 is a crucial regulator of an
autoregulatory feedback loop important in preventing the stochastic expression of WNT family members.
The importance of WNT signaling as regulators of metastatic progression are discussed later in this review.
However, Nkd1 itself is a specific regulator of clock and is regulated in an oscillatory manner by a number
of factors. This also implies H19 synergizes with WNT/NKD1 signaling to regulate the circadian rhythm
pathways essential for proper vertebrate embryogenesis, but also the molecular clock genes that provide
important spatial information for the inappropriate re-activation of embryonic genes that induce tumorigenic
processes such as proliferation, invasion, angiogenesis, as well as EMT [133,134] .

Understanding the regulation of H19 is important as certain types of cancer are dependent upon H19. In
fact, BC-819 is an approach utilizing a plasmid expression system coding for diphtheria toxin under the
control of an H19 regulatory sequence. Intratumoral injection of BC-819 in vivo as well as intraperitoneal
(IP) injection of the compound in ovarian cancer patients is undergoing phase I/II clinical trials and shows
promise at extending survival rates by reducing tumor burden [135-137] . Additional clinical trials include the
ectopic expression of BC-819 via intravesical instillation in bladder cancer patients, and BC-819 vaccination
in combination with gemcitabine for those with pancreatic adenocarcinoma. While both trials show promise
as an effective approach to deliver lncRNAs in cancer patients [135-137] , it will be interesting to determine the