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(loss of E-cadherin and gain of N-cadherin, vimentin, and tumor necrosis factor-α, interleukin-6 (IL-6), and Ezrin]
slug) dependent on transforming growth factor-β (TGF-β). that are required for angiogenesis and metastasis in T24
Similarly, MALAT1 was found highly expressed in cancer cells. Furthermore, H19 is highly expressed in most
[59]
stem cells (CSCs) of pancreatic cancer and knockdown of cases of bladder carcinoma which subsequently metastasize
MALAT1 in those cells greatly reduces CD133+ population compared to those that do not metastasize. Similarly, H19
and sphere formation, suggesting an important role of level is substantially higher in invasive bladder carcinoma
[49]
CSC formation which may help in migration and survival cell lines than non-invasive cell lines. Mechanistically, H19
of cells during metastasis. recruits EZH2 in the promoter region of Nkd1 (an antagonist
gene of Wnt/β-catenin) and suppresses its transcription by
HOX transcript antisense RNA hyper-methylation. This makes Wnt/β-catenin constitutively
active while E-cadherin is suppressed, leading to metastasis
HOTAIR stands for HOX transcript antisense RNA with of bladder cancer. In addition to alterations in the gene
[60]
2.2 kb in length. It is derived from HOX C gene (which expression pattern, H19 also enhances the interaction of the
determines anterior and posterior plane during embryonic tumor cell with extracellular matrix. MDA-MB-231 cells
development). High expression of HOTAIR is correlated growing in three-dimensional culture exhibit high level
with metastasis, and it signifi cantly decreases the chance of H19, which helps in enhanced scattering of the cells,
of survival of those patients. Overexpression of HOTAIR suggesting a role of H19 in breast cancer metastasis.
[61]
in different cell lines increases cell invasion and transforms In addition to bladder and breast cancer, H19 may also
non-invasive cells into invasive cells in vivo. Similarly, contribute to metastasis of colorectal cancer. For instance,
overexpression of HOTAIR in breast cancer MDA-MB-231 H19 is highly expressed in methotrexate resistant HT-29 cells
cells increases metastatic lung nodules by a 10-fold as which reveal mesenchymal morphology. Overexpression
compared to control. [50] of H19 increases the EMT markers vimentin, ZEB-1, and
ZEB-2 and also promotes cell migration. [62]
Like many other lncRNAs, HOTAIR impacts metastasis via
chromatin remodeling. HOTAIR can directly bind to PRC2 Nuclear factor-κB interacting lncRNA
and LSD1, a demethylase that fl anks HOXD. This binding
coordinates enrichment of EZH2 in HOXD promoter which Nuclear factor-κB (NF-κB) interacting lncRNA (NKILA)
causes methylation of H3K27, leading to silencing of is a 2.5 kb transcript mostly found in the cytoplasm and
transcription through HOXD gene. A similar mechanism it negatively regulates the NF-κB signaling. NF-κB is a
[51]
[63]
was also observed in the metastatic breast cancer cell lines, transcription factor which mediates inflammatory signaling
where HOTAIR helps in PRC2 occupancy on promoter of pathways and is often constitutively active in various cancer
hundreds of genes and silences them by trimethylation of cells. NF-κB is in an active (phosphorylated) or inactive
[64]
H3K27. Many of those genes are involved in breast cancer
progression, cell adhesion, and metastasis. [50] state (dephosphorylated) in the cell. In the inactive state,
the dimer NF-κB (p65 and p50) is bound with an inhibitory
In addition to breast cancer metastasis, HOTAIR has subunit IκB. This complex keeps the dimer in the cytoplasm
been attributed to enhance metastasis in oral squamous by masking the nuclear localization signal. Several external
cell carcinoma by suppressing the level of E-cadherin. stimuli activate IKKβ which phosphorylates IκBα (a subunit
[52]
Moreover, HOTAIR along with miR-196a is also associated of IκB) and leads to proteasomal degradation of IκBα. Now,
with high-risk metastasis and poor survival of a patient with the free NF-κB dimer translocates to the nucleus where it
gastrointestinal stromal tumors. [53] binds to NF-κB response element and activates transcription
of different genes. Thus, NKILA adds a new layer of
[65]
H19 regulation for NF-κB activity, by interacting with IκBα and
masking its phosphorylation site from IKKβ. This prevents
H19 is one of the first lncRNAs identified in early phosphorylation of IκBα and translocation of NF-κB dimer
1980 and its expression is in accordance to expression from the cytoplasm to the nucleus.
of α-fetoprotein. This gene represents a maternally
[54]
imprinted gene in both humans and mice. The expression The highly metastatic breast cancer cell lines express a very low
of H19 gradually decreases from fetal tissue to adult, which level of NKILA while less aggressive breast cancer cell lines
indicates its importance in embryo development. [55] Initial exhibit a high level of NKILA. Furthermore, overexpression
reports suggested that H19 could work as a tumor suppressor of NKILA in MDA-MB-231 cells reduces their metastasis
in different cancer cases; however, other studies in the lung, liver, and lymph nodes. In contrast, knockdown
[56]
suggested that H19 expression is high in tumor tissues. [57,58] of NKILA in MCF-7 cells increases their metastasis to those
Despite high expression in tumor samples, overexpression distant sites. Clinically, loss of NKILA is associated with
of H19 in T24 bladder carcinoma cell line did not provide advanced breast cancer and distant metastases; low expression
proliferative advantage. This implies that H19 may regulate of NKILA is associated with the patient survival. Therefore,
[63]
metastasis rather than formation of primary tumor. Indeed, NKILA can predict the outcome of breast cancer and may
overexpression of H19 up-regulates genes [e.g. uPAR, serve as a prognostic marker.

Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ Issue 1 ¦ January 15, 2016 ¦ 5