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Page 12 of 23 Parsons et al. J Cancer Metastasis Treat 2018;4:19 I http://dx.doi.org/10.20517/2394-4722.2018.11
binding protein 1 (IGF2BP1), as well as members of the protein kinase A (PKA) signalling pathway [146,149] .
Going forward, HULC shows promise as a therapeutic target for patients with metastatic disease, and
therefore further investigation is warranted.
Estrogen receptor regulated lincRNA 01
The role for lncRNAs regulating hormone-signaling pathways related to the metastatic cascade are less well
understood. In general, 17β-estradiol is known to regulate the activity and abundance of TGFβ signaling [150,151] ,
as well as modulate the levels of E-cadherin . Together, 17β-estradiol, and moreover active ERα signaling
[152]
are crucial in maintaining an epithelial phenotype by suppressing the pathways associated with EMT.
17β-estradiol/ERα signaling also controls the activity of certain ncRNAs, such as the miR-200 family of
miRNAs, which regulates EMT promoting TF regulators such as ZEB1 and Smad interacting protein 1
(SIP1) . This indicates steroid hormone signaling pathways can modulate ncRNA networks responsible for
[31]
tumorigenesis and metastatic dissemination. For instance, our group identified lncRNA estrogen receptor
regulated lincRNA 01 (ERRLR01) as a prognostic biomarker in breast cancer, which is regulated by ERα
activity in breast cancer tumors. Specifically, ERRLR01 is highly expressed in triple-negative breast cancers,
yet not in samples derived from patients with ERα+ tumors. Follow up experiments indicated 17β-estradiol
also altered the levels of ERRLR01 in ERα+ cells lines (i.e., MCF-7 and T47D) [25,153] .
Given 17β-estradiol is a crucial regulator of EMT , we surmise ERRLR01 and other lncRNAs are crucial
[28]
mediators of the metastatic cascade. Another example of a hormone-sensitive lncRNA is linc00461, which
modulates the activity of CREB, a known 17β-estradiol regulated TF. Interestingly, linc00461 interacts with
miR-9 as a sponge releasing miR-9 from its cognate mRNA targets, thereby altering the activity of CREB,
and subsequently modulating the proliferation and migration of glioma cells . linc00461 also regulates
[154]
tumorigenic and metastatic phenotypes in melanoma cells , therefore further work elucidating the
[155]
mechanism of action for linc00461 is warranted.
Colon cancer associated transcript 2
The lncRNA colon cancer associated transcript 2 (CCAT2) was first discovered via genome-wide SNP-
association studies whereby investigators determined if particular genomic variants associated with cancer
incidence . Previously many SNPs remain understudied because they occur within the ncRNA region of
[156]
the genome. With our current understanding of the ncRNA landscape, new variants are being reassessed for
functional significance in cancer. SNP, rs6983267, was of particular interest as this variant maps to the 8q24
region of the genome, which correlates with higher incidences of a number of epithelial tumors, including
colorectal, prostate, ovarian, and inflammatory breast cancer . Subsequent studies indicate CCAT2 levels
[157]
are expressed at higher frequencies in tumor samples from colorectal cancer (CRC) patients with metastatic
disease [111,156,158,159] . CCAT2 is also highly expressed in small cell lung cancer (SCLC) samples and is highly
correlated with poor prognosis, as well as the presence of metastasis, signifying CCAT2 is an independent
prognostic biomarker and/or therapeutic target for a disease with limited therapeutic options.
The regulatory mechanisms by which CCAT2 controls the progression of metastatic events is still unclear.
Gain- or loss-of-function studies demonstrate that CCAT2 can modulate the proliferation and invasion
potential of cancer cells in vitro, as well as the number of micro-metastatic lesions at distant organ sites
utilizing murine xenograft models. However, the only reported cellular mechanism of action by which
CCAT2 alters the metastatic potential of cells involves WNT signaling. The WNT gene family are crucial
regulators of metastatic progression as WNT coupling to Frizzled receptors on the cell surface allows for the
release of β-catenin from the GSK-3β ubiquitination complex [160,161] . β-catenin then enters the nucleus and
operates as a transcriptional co-activator along with TCF/LEF, which together promotes the transcription
of genes supporting metastatic progression. Here, CCAT2 overexpressing cell lines harbor increased WNT
activity, while siRNAs directed towards CCAT2 reduced both the nuclear and cytoplasmic abundance of