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date. EMT was fi rst reported in this malignancy two Table 1: EMT TFs in gastroenterological malignancies
decades ago, and the major functional interactions of TFs EC GC CRC HCC PDCA CCA
the EMT-transcription factors have also been reported. ZEB1/2 [16,17] [63] [64] [54]
The genomic landscape of pancreatic cancer has been Twist1 [25] [65]
partially unveiled. However, the role of each key Snail [11] [23,24,66] [65]
[53]
molecule involved in EMT remains to be elucidated, SHP-1 [67]
an effective therapeutic molecular target is yet to be SMAD3/4 [5] [56]
identifi ed for pancreatic cancer. The epigenetic analysis FoxC1 [68]
revealed that the Class I histone deacetylase inhibitor FoxC2 [69]
mocetinostat suppresses ZEB1 and induces miR-203 FoxM1 [70,71]
re-expression, thus, leading to the repression of stemness FoxQ1 [72]
[54]
properties and drug resistance. TGF-β1 was highly NFATc1 [57]
[55]
up-regulated in pancreatic cancer. TGF-β1 has been EC: Esophageal carcinoma; GC: Gastric cancer; CRC: Colorectal
shown to induce EMT, SMAD2/3 phosphorylation, cancer; HCC: Hepatocellular carcinoma; PDCA: Pancreatic ductal
adenocarcinoma; CCA: Cholangiocarcinoma; SMAD: Mothers
restoration of retinoblastoma 1 expression and against decapentaplegic homolog; ZEB1/2: Zinc fi nger E-box binding
SMAD-dependent up-regulation of Wnt7b in KRC 1/2; TFs: Transcription factors; EMT: Epithelial-mesenchymal
cell line. In in vivo orthotopic models, inhibition of transition; NFATc1: Nuclear factor of activated T cells; SHP-1: Small
TGF-β1 signaling suppressed those effects, resulting heterodimer partner-1
in tumor regression and decrease in metastasis.
[56]
The calcium-/calcineurin-responsive nuclear factor Table 2: MicroRNA in gastroenterological malignancies
of activated T cells, a transcription factor expressed MicroRNA Targets EC GC CRC HCC PDCA CCA
during infl ammation, drives EMT in a sex determining miR7 IGF1R [18]
region-box 2-dependent manner and loss of p53 induced miR9 CDH1 [73]
EMT, and acquisition of cancer stem cell-like properties miR34a/b/c ZNF281 [24]
by down-regulating miR-200c. Ataxia telangiectasia miR125b SMAD2/4
[57]
Group D complementing gene, which is highly expressed miR130b IRF1 [74]
[58]
in pancreatic cancer, up-regulated CD44 in mouse miR146a Numb [66]
and human PanIN lesions via activation of β-catenin miR148a Snail [75]
signaling. This in turn results in the induction of EMT miR200b/c ZEB1, [16,17] [28] [35] [76] [46]
NCAM1
phenotype and expression of ZEB1 and Snail1. [59]
miR212 MnSOD [29]
Perspectives miR216a/217 PTEN/ [36]
SMAD7
Increasing evidence supports the role of EMT in cancer miR223 Fbw7 [77]
progression, metastasis and drug resistance. Recent miR331-3p PHLPP [37]
studies of EMT transcription factors and microRNAs are miR338-3p ZEB2 [78]
shown in Tables 1 and 2 respectively. In a tumorigenic miR424-5p ICAT/ [38]
mouse model, it was shown that EMT precedes CTNNBIP1
pancreatic tumor formation. However, whether EMT miR655 ZEB1 [79]
[60]
occurs in the early stage or late stage of tumor formation lncRNA ZEB1/2 [40]
remains to be confi rmed. The mesenchymal phenotype EC: Esophageal carcinoma; GC: Gastric cancer; CRC:
is essential for tumor cell migration and invasion. The Colorectal cancer; HCC: Hepatocellular carcinoma; PDCA:
epithelial phenotype might be required for cancer cells to Pancreatic ductal adenocarcinoma; CCA: Cholangiocarcinoma;
PHLPP: PH domain and leucine-rich repeat protein phosphatase;
spread to other organs. Cancer cells tend to acquire both SMAD: Mothers against decapentaplegic homolog; PTEN:
phenotypes under specifi c conditions, and the functional Phosphatase and tensin homolog; IGF1R: Insulin-like growth
aspect of each phenotype regarding chemoresistance factor-1 receptor; ZNF281: Zinc finger protein 281; IRF1:
remains elusive. EMT has been categorized into Interferon regulatory factor 1; ZEB: Zinc fi nger E-box binding;
[61]
three types: developmental (Type I), fi brosis and wound NCAM1: Neural cell adhesion molecule; MnSOD: Manganese
healing (Type II), and cancer (Type III). Of these, superoxide dismutase
Type III EMT is the least well understood. If Type III
[62]
EMT can be classifi ed further into subgroups based Confl icts of interest
on the molecular mechanisms, it would be possible to There are no confl icts of interest.
develop personalized cancer therapeutic approaches
based on the specifi c EMT stage. References
Financial support and sponsorship 1. Tam WL, Weinberg RA. The epigenetics of
epithelial-mesenchymal plasticity in cancer. Nat Med
Nil. 2013;19:1438-49.

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