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LncRNA-ATB found in lung squamous carcinoma and colorectal cancer
as compared to adjacent normal tissue. Overexpression
This lncRNA is activated by cytokine TGF-β (lncRNA- of lncRNA-LET suppresses metastasis of HCC and colon
[72]
ATB) that is well-known for its role in tumor metastasis. cancer cells in vivo. LncRNA-LET could limit HCC
TGF-β modulates different signaling pathways involved in metastasis in both hypoxic and normoxic condition by
EMT, migration, invasion, and metastasis. [66-68] A long time different mechanisms. In hypoxic condition, lncRNA-
treatment of cells with TGF-β induces EMT (decreased LET interferes with the function of hypoxia-inducible
E-cadherin and increased N-cadherin, vimentin, slug, twist1, factor-1α (HIF-1α), a transcription factor that regulates
ZEB-1 and ZEB-2). Similar treatment of hepatocellular a number of genes under tumor hypoxia, and promotes
carcinoma (HCC) cells with TGF-β activates the lncRNA- angiogenesis and metastasis. The high expression of
[73]
ATB in a time- and dose-dependent manner. Clinically, lncRNA-LET suppresses HIF-1α through inhibiting NF90
lncRNA-ATB level is high in HCC tumors as compared to which is required for accumulation of HIF-1α mRNA.
adjacent normal tissue. Similarly, a high level of lncRNA- However, hypoxia keeps the level of lncRNA-LET low by
ATB is positively correlated with microvascular invasion deacetylating its promotor. As a result, HIF-1α is increased
and portal vein tumor thrombosis. Consistent with these promoting metastasis. In normoxic condition, lncRNA-
observations, injection of HCC tumor cells overexpressing LET inhibits expression of CDC42 (which is required for
lncRNA-ATB into orthotropic mice promotes metastasis trans-endothelial migration) of circulating tumor cells. The
to different organs. One of the possible mechanisms is low level of lncRNA-LET in HCC keeps CDC42 high and
[69]
through enhancement of EMT by interfering the action of this results in profound metastasis of HCC. [72]
miR-200 which can inhibit EMT by suppressing ZEB-1 and
ZEB-2. This 2.5 kb long lncRNA carries 6 binding sites Colon cancer-associated transcript 1
[70]
for miR-200. Therefore, lncRNA-ATB traps miR-200 and
prevents degradation of ZEB-1 and ZEB-2 by miR-200. The Colon cancer-associated transcript 1 (CCAT1) was found
high level of ZEB-1 and ZEB-2 ultimately promotes EMT up-regulated in colon cancer tissue, circulating blood cells
and invasiveness of different cells in vitro and in vivo. In of colon cancer patient and metastasis cases, indicating its
[74]
addition, lncRNA-ATB enhances colonization of migrating role in colon cancer progression. Besides, high expression
cells by enhancing the function of IL-11-STAT3 signaling of CCAT1 is also associated with primary tumor tissue,
pathway. In this case, lncRNA-ATB binds to IL-11 mRNA lymph node metastasis, and metastatic cases of gastric
and stabilizes it. The increased stability of IL-11 facilitates carcinoma. The elevated level of CCAT1 reduces the
[75]
its secretion. As a ligand, IL-11 promotes phosphorylation survival of HCC patients. In both gastric cancer and HCC cell
of STAT3. This autocrine mitogenic signal helps in robust lines, overexpression of CCAT1 enhances the proliferation
cell survival and effective colonization in distant organs. [69] and migration of cells driven by c-Myc, an oncogenic
transcription factor required for cell survival. On one hand,
LncRNA-low expression in tumor c-Myc binds to promoter of the CCAT1 and up-regulates its
level in cancer cells. On the other hand, CCAT1 prevents
[75]
Low expression in tumor (LET) was originally identified in degradation of c-Myc by interaction with let-7, a known
HCC cells. Along with HCC, a reduced level of LET is also miRNA that can target c-Myc through its 3’-UTR. [76]
[71]

Figure 2: Long non-coding RNAs involved in different stages of cancer metastasis

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