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IL-6-dependent activation of signal transducer and EMT and metastasis in HCC. The zeb1-as1 promoter
activator of transcription 3 (STAT3), a conserved and was hypomethylated in human HCC samples and
direct target of miR-34a. Stimulation of EMT results in resulted in tumor specifi c up-regulation of ZEB1-AS1.
[26]
[39]
the nuclear translocation of pyruvate kinase M2 (PKM2) lncRNA-AL589182.3 (ENST00000493038), which can
in colon cancer cells. EMT stimulation causes direct be activated by TGF-β, up-regulated ZEB1 and ZEB2
interaction of PKM2 in the nucleus with TGF-β-induced through competitively binding to the miR-200 family and
[40]
factor homeobox 2, a transcriptional cofactor repressor induced tumor cell EMT and invasion. Interestingly,
[27]
of TGF-β signaling. The roles of miRNA in EMT in hepatitis C virus (HCV) has also been found to contribute
CRC have been reported. For example, liver metastatic to EMT. HCV core protein down-regulated secreted
tissues showed higher expression of miR-200c than that frizzled-related protein 1 (SFRP1) expression by inducing
of the primary tumor, and miR-200c overexpression hypermethylation of the SFRP1 promoter. A previous
[41]
was signifi cantly associated with hypomethylation of transgenic mouse study demonstrated that overexpression
[28]
the miR-200c promoter. Overexpression of miR-212 of HCV core protein in HCC cells increased active
inhibited CRC cell migration and invasion in vitro and TGF-β levels in culture supernatants and induced
intrahepatic and pulmonary metastasis in vivo. Manganese SMAD2/3 phosphorylation. HCC cells expressing HCV
SOD (MnSOD) was identifi ed as a direct target of core protein could activate stellate cells in co-culture and
miR-212, and an inverse correlation has been observed this activation was TGF-β-dependent. CD44s, a known
[42]
between the level of miR-212 and MnSOD protein in cancer stem cell marker in many malignancies, mediated
colorectal tumor samples. MnSOD was required for TGF-β-induced EMT, and regulated mesenchymal
down-regulation of epithelial markers and up-regulation phenotype in HCC. [43,44]
of mesenchymal markers in CRC cells. [29]
Cholangiocarcinoma
Hepatocellular Carcinoma Since this disease is not common, clinical and basic

TGF-β is a major microenvironmental factor to affect research on human cholangiocarcinoma (CCA) samples
hepatocellular carcinoma (HCC) dedifferentiation, is limited. CCA is one of the solid cancers that have no
inducing EMT and acquisition of metastatic phenotypes. effective molecular targeted therapy to date. Gemcitabine
Transcriptomic analysis on human HCC tissue samples plus platinum is the only chemotherapeutic drug that
[45]
revealed that TGF-β signaling was activated in a to some extent inhibits CCA progression. Several
subpopulation of HCC, called Wnt-TGF-β subclass. [30,31] EMT-related molecules are also known to play pivotal
Sequential transcriptome analysis suggested that TGF-β roles in CCA. Inactivation of miR-200c is reported
signaling was a late event accompanied with extensive to induce the expression of mesenchymal markers
gene alterations. TGF-β has been shown to induce and NCAM1, a known hepatic stem/progenitor cell
[32]
[46]
hepatocyte nuclear factor-4α (HNF-4α) post-translational marker. STAT3-driven expression of small proline-rich
modifi cations that correlate with the early loss of the protein 2a suppressed the interaction of miR-200c/141
[47]
ability of HNF-4α to bind to target gene promoters with ZEB1. Although the effi cacy of the EGFR
via glycogen synthase kinase-3β (GSK-3β) kinase tyrosine kinase inhibitors, erlotinib and cetuximab, has
[48]
during EMT. The receptor tyrosine kinase Axl not been confi rmed in CCA treatment, activation of the
[33]
binds to 14-3-3ζ as a result of phosphorylation of the EGF-EGFR axis is known to abolish gefi tinib-mediated
[49]
linker region of SMAD3 at Ser213, which causes the EMT progression. ANXA8 was found to be involved
up-regulation of TGF-β target genes such as PAI1, in EGF-forkhead box protein O signaling-mediated
[50]
[34]
MMP9 and Snail. The function of EMT transcription EMT progression. The sonic hedgehog ligand is
factors have been updated recently. Accumulative highly expressed in human CCA, and treatment with the
data on non-coding RNA have revealed a novel hedgehog inhibitors, cyclopamine and 5E1, suppressed cell
mechanism of EMT in HCC. For example, miR-200c proliferation, migration and invasion by down-regulating
was down-regulated in HCC with bile duct tumor the target genes hepatoblastoma 1 and 2. Furthermore,
[51]
thrombus, which occurred in 30 out of 1,240 patients, these inhibitors have been shown to attenuate EMT. In
and regulated ZEB1 expression as well as an invasive addition to the above-mentioned molecules, some unique
phenotype. The miR216a/217 cluster induced EMT molecules have also been linked to EMT recently in
[35]
and its direct targets, phosphatase and tensin homolog CCA, which include 4 histamines (H1-H4) and their
and SMAD7 were identifi ed. miR-331-3p-mediated receptor (HR). Loss of H3HR expression or overexpression
[36]
inhibition of PH domain and leucine-rich repeat protein of H4HR has been shown to signifi cantly decrease CCA
phosphatase resulted in stimulation of protein kinase proliferation and disrupt EMT progression. [52]
B (AKT) and subsequent EMT. miR-424-5p reversed Pancreatic Cancer
[37]
resistance to anoikis, blocked EMT progression and
inhibited its direct target ICAT/CTNNBIP1, a novel Pancreatic cancer is one of the worst solid cancers in
β-catenin-interacting protein. A non-coding antisense terms of prognosis and treatment outcome, because
[38]
transcript, ZEB1-antisense1 (ZEB1-AS1), promoted there is no promising molecular target identifi ed to
Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 3 ¦ October 15, 2015 ¦ 185