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senescence program. Epithelial cell adhesion migration and invasion in GC cells. [17] miR-7, which
[7]
molecule (EpCAM), a well-known marker for is down-regulated in highly metastatic GC cell lines,
circulating tumor cells in many solid tumors, is was found to be involved in metastasis by regulating
down-regulated in TGF-β1-mediated EMT. However, its direct target, insulin-like growth factor-1 receptor.
EpCAM expression in disseminated tumor cells (DTCs) Overexpression of miR-7 was able to suppress
was associated with lymph node metastasis and Snail expression, increase E-cadherin expression
decreased overall survival of patients with EC. The and partially reverse EMT. [18] Several other EMT
confl icting evidence that DTCs need the process of inducers have been reported recently. For example,
EMT but express epithelial cell marker EpCAM is erythropoietin-producing hepatocellular (Eph) A2
supported by the result that high expression of EpCAM overexpression resulted in up-regulation of the EMT
promoted tumor outgrowth after xenotransplantation of markers N-cadherin and Snail, and the Wnt/β-catenin
esophageal carcinoma cells, suggesting that EpCAM targets TCF4, Cyclin-D1 and c-Myc. In contrast, Eph
expression changes dynamically over the course during A2 silence by short hairpin RNA had the opposite
cancer progression. [8] effect. [19] SALL4, a zinc-fi nger transcriptional factor for
embryonic stem cell's self-renewal and pluripotency,
A notable EMT inducer that has recently been has been suggested to be involved in tumorigenesis.
reported is interleukin-23 (IL-23). IL-23 is mainly SALL4 overexpression induced EMT with increased
produced by Th17 cells that infi ltrate in the tumor expression of Twist1 and N-cadherin, and decreased
microenvironment and contributes to EMT via activation expression of E-cadherin. [20] Telomerase activation
of the Wnt/β-catenin pathway in esophageal squamous through induction of human telomerase reverse
carcinoma. Eukaryotic initiation factor 5A2 (eIF5A2) transcriptase (hTERT) induced malignant transformation
[9]
was fi rst isolated as an oncoprotein and was later by stabilizing telomeres. hTERT overexpression could
found to be involved in EMT. Increased expression of promote EMT and stemness of GC cells. TGF-β1 and
eIF5A2 induced ESCC metastasis and angiogenesis β-catenin-mediated EMT was abolished by depletion
via the hypoxia inducible factor-1 signaling pathway of hTERT. [21] In the gastric epithelium, the runt
in esophageal squamous cell lines. The clinical domain transcription factor RUNX3 functions as a key
[10]
investigation revealed Snail overexpression in 40% of mediator of the TGF-β pathway. Loss of RUNX3 in
patients with SCC tissue samples, which was associated gastric epithelial cells results in EMT and production
with vascular invasion, advanced clinical stage and the of tumorigenic stem cell-like subpopulation expressing
EMT phenotype. [11] gastric stem cell marker Lgr5. Loss of both RUNX3
and p53 caused gastric epithelial cells to be sensitized
Gastric Cancer
to TGF-β-induced EMT, during which the resultant
Distinct carcinogenetic pathways have been reported induction of Lgr5 is enhanced by aberrantly activated
for intestinal and diffuse type gastric carcinoma, Wnt pathway. [22]
but EMT has been mainly discussed for the latter
phenotype. [12] The link between EMT and gastric Colorectal Cancer
adenocarcinoma could be partly because of the H. pylori EMT is critical in transdifferentiation of polarized
cytotoxin-associated gene A (CagA) oncoprotein, epithelial cells to an invasive mesenchymal phenotype.
which is responsible for the “hummingbird” phenotype The function of EMT transcription factors in colorectal
in vitro, which mimics EMT. [13] CagA overexpression cancer (CRC) has been reported. Snail, an activator
in gastric cancer (GC) cells up-regulated the expression of EMT, was expressed at high levels in CRC
of mesenchymal markers and CD44, which is a cancer colonospheres. Overexpression of Snail in CRC cells
stem cell marker in GC. [14] CagA overexpressing induced colonosphere-forming property and cell
cancer cells also showed high tumorigenic ability dedifferentiation. Blocking IL-8 expression or activity
in vivo. Immunohistochemical analysis of samples disrupted the Snail-induced stem cell-like features of
from individuals with H. pylori infection confi rmed colonospheres. Snail directly induced zinc fi nger
[23]
high CD44 expression and expression of different protein 281 (ZNF281) transcription and repressed
mesenchymal markers. [15] Tissue microarray analysis miR-34a/b/c, thereby protection of ZNF281 mRNA from
of samples from 385 GC patients revealed three direct down-regulation by miR-34. Furthermore, p53
miRNAs (miR-200c, miR-200b and miR-125b) to activation resulted in miR-34a-dependent repression of
be signifi cantly associated with survival. Functional ZNF81. Syngeneic Twist1-positive colon carcinoma
[24]
experiments in a mouse model demonstrated that cells (CT26) that invaded tissues surrounding tumors
miR-200b suppressed ZEB1 and E-cadherin and demonstrated the mesenchymal phenotype. Genotype
[25]
inhibited cell migration and tumor growth. [16] In vitro also affected the mechanism of EMT. TGF-β1 induced
analysis revealed that overexpression of miR-200b changes in cell morphology, gene expression, motility
also down-regulated ZEB2 expression, which in and invasion consistent with EMT in microsatellite
turn signifi cantly reduced cellular proliferation, stable colon cancer cells, whereas cells exhibited

184 Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 3 ¦ October 15, 2015 ¦