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specificity of BC-819 in mitigating the number of metastatic foci detectable in these patients or if this therapy
extends tumor latency.

SPRY4 intronic transcript 1
Recently, SPRY4 intronic transcript 1 (SPRY4-IT1) was reported as a novel lncRNA crucial in regulating the
initiation and progression of EMT across a number of epithelial carcinomas . SPRY4-IT1 is transcribed
[138]
from an intronic region within the SPRY4 gene and is approximately 708bp in length. SPRY4-IT1 is unique
in that this lncRNA contains several known hairpin structures that associate with particular RBPs .
[139]
Therefore, investigators have some notion regarding the mechanisms by which SPRY4-IT1 controls cellular
processes important in supporting a metastatic phenotype and includes altering the expression of regulatory
genes such as MCM2, XIAP, LPIN2 . Functional studies indicate that aberrant expression of SPRY4-IT1
[138]
also modulates the migratory and invasive capacities across a number of in vitro cancer models and does this
in part by regulating DNA repair genes, such as MDM2 and CDK1.

SPRY4-IT1 also controls the process of EMT through the modulation of intermediate filament proteins, such
as fibronectin and vimentin, resulting in the fine-tuning of the molecular inputs initiated by Snail and TGF-β
localization and activity. Specifically, in esophageal squamous cell carcinoma (ESCC), the overexpression of
SPRY4-IT1 disrupts the nuclear localization of Snail, and facilitates TGF-β-induced EMT [140-142] . Mechanistically,
it is still unclear as to how SPRY4-IT1 reduces the expression of epithelial cadherins (i.e., E-cadherin), while
subsequently promoting the expression of neuronal or mesenchymal cadherins (i.e., N-cadherin). SPRY4-
IT1 is known to modulate gene activity via dampening global H3K27me3 distribution, which is not in of
itself not biologically informative; however, SPRY4-IT1 can induce H3K27me3 methylation of the EZH2
gene promoter, and subsequently promote the repression of E-cadherin gene expression . This post-
[143]
transcriptional chaperone activity of chromatin modifying complexes to particular gene loci is a typical
feature of lncRNAs and is crucial in dampening unwarranted transcripts during cellular development.

It would also be interesting to determine if SPRY4-IT1 interacted with a selective subset of miRNAs that
supported the development of angiogenesis. For instance, miR-126 inhibits tumor growth and results in
decreased micro-vessel density in cervical cancer [144,145] . SPRTY-related proteins, such as SPRED1 have been
reported to bind to miR-126 and control tumor neo-angiogenesis, as well. Therefore SPRY4-IT1 may be a
crucial component of the ncRNA network responsible for tumor neo-angiogenesis.

Highly upregulated in liver cancer
Highly upregulated in liver cancer (HULC) was first identified in hepatocellular cancer and is highly
expressed in liver cancer, as well as in a number of carcinomas that metastasize to the liver, including colon
and breast cancer [146,147] . Two recent studies suggest that HULC promotes angiogenesis as well as neo-angiogenesis,
essential processes in the progression of metastasis as micro-metastatic lesions require an oxygen-rich environment
to meet the demand of tumor growth within an hypoxic environment. For instance, Zhao et al. found that
[148]
overexpression of HULC in hepatocellular cancer cells results in an increase in the pro-angiogenic factor
SPHK1. Specifically, HULC functions by sequestering miR-107, a bona fide target of which is the TF E2F1.
The derepression of E2F1 results in the enhanced transcription of SPHK1, and by extension enhanced rates
of vessel tube formation as well as increased tumor burden in a murine xenograft model. This HULC-
specific upregulation of angiogenic processes was further tested in a chicken chorioallantoic membrane
(CAM) assay, whereby condition medium from HULC overexpressing cells promoted increased growth of
vessels within the chicken embryo.

Additional mechanisms by which HULC induces angiogenesis includes the sponging of miR-372 away
from genes important in modulating the growth and survival of cancer cells. Additionally, HULC itself is
transcriptionally upregulated by pro-metastatic growth factors, receptors, and RBPs including IGF2 mRNA-