Journal List > Korean J Gastroenterol > v.56(2) > 1006763

Kim, Han, and Park: The Role of Epithelial-mesenchymal Transition in the Gastroenterology

Abstract

The epithelial-mesenchymal transition (EMT) plays physiologic roles in the embryogenesis, wound healing, and tissue regeneration. In terms of pathological direction, it causes organ fibrosis, cancer development, progression, metastasis, and chemoresistance. Recently, the underlying mechanism of EMT and many kinds of EMT regulators have been identified. Pharmaceutical treatment strategies which target EMT pathway could be applied for the prevention of tissue fibrosis and cancer progression. In the field of gastroenterology, profuse evidences have been collected about the critical roles of EMT in cancers of the gastrointestinal tract, liver, and pancreas and hepatic fibrosis. However, EMT varies widely among cancer types, and much remains to be identified about the main regulators of EMT in a specific disease. In this review, we present recent research results regarding the roles of EMT in cancers and organic fibrosis, especially in the area of gastroenterology.

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Fig. 1.
EMT and MET in normal and diseased condition. The EMT and MET is involved in embryonic development, organ formation, wound healing, tissue regeneration, organ fibrosis, cancer progression, and metastasis. EMT, epithelial-mesenchymal transition; MET, mesenchymal-epithelial transition.
kjg-56-69f1.tif
Fig. 2.
Epithelial cell plasticity can be viewed as a form of ei-ther transdifferentiation or EMT. Type 1 EMT is seen during development or organ formations. Type 2 EMT is seen when epithelial cells populate interstitial spaces with resident or inflam-mation-induced fibroblasts. Type 3 EMT is part of the metastatic process, whereby epithelial tumor cells detach a primary tumor nodule, migrate to a new tissue site, and reform as a secondary tumor nodule. (Adapted from Zeisberg and Neilson.1).
kjg-56-69f2.tif
Fig. 3.
Signal pathways regulating the epithelial-mesenchymal transition (EMT). TGF-β signals toward the SMAD pathway or the PI3K/AKT axis. Wnt ligands block β-catenin degradation. Excess β-catenin enters the nucleus and upregulates slug and snail transcription. In integrin signaling, overexpression of ILK leads to nuclear translocation of β-catenin. Signals via RTK lead to EMT through the Ras-Raf-MAPK pathway or the PI3K/AKT pathway. AKT, serine/threonine kinase; GSK-3β, glycogen synthase kinase-3β; H/E (Spl), Hairy and enhancer of split; ILK, integrin-linked kinase; MAPK, mitogen-activated protein kinase; NF-κ B, nuclear factor-κ B; PI3K, phosphatidylinositol 3’ kinase; RTK, receptor tyrosine kinase; TGF-β R, transforming growth factor-β receptor; ZEB1, zinc finger E-box binding homeobox 1 (Adapted from Iwatsuki et al.18).
kjg-56-69f3.tif
Table 1.
Markers Regulating EMT Pathways
Acquired markers Attenuated markers
Name EMT type Name EMT type
Cell surface proteins
N-cadherin 1, 2 E-cadherin 1, 2, 3
Cytoskeletal markers
FSP1 1, 2, 3 Cytokeratin 1, 2, 3
α-SMA 2, 3
Vimentin 1, 2
β-Catenin 1, 2, 3
ECM proteins
α1(I)-, 1, 3 α1(IV)-collagen n 1, 2, 3
α1(III)-collagen
Laminin 5 1, 2 Laminin 1 1, 2, 3
Fibronectin 1, 2
Transcription factors
Snail 1 (Snail) 1, 2, 3
Snail 2 (Slug) 1, 2, 3
ZEB1 1, 2, 3
Twist 1, 2, 3
MicroRNAs
miR10b 2 Mir-200 family 2
miR-21 2, 3

  EMT, epithelial-mesenchymal transition; FSP, fibroblast specific protein; SMA, smooth muscle actin; ECM, extracellular matrix; ZEB1, zinc finger E-box binding homeobox 1.

Table 2.
Studies about the EMT Regulators in Gastrointestinal Cancers
EMT associated regulators Study materials Authors, year
Esophageal squamous cell carcinoma
Slug Human tissues Uchikado et al. 200527
Snail Human tissues Natsugoe et al. 200728
Twist Human tissues, cell lines Yuen et al. 200729
Esophageal adenocarcinoma
Snail Human tissues, cell lines Rosivatz et al. 200631
Slug, Snail, Twist Human tissues, cell lines Jethwa et al. 200830
Gastric carcinoma
Snail, SIP1, Twist Human tissues Rosivatz et al. 200233
Slug, Snail, Twist, SIP1 Human tissues Castro et al. 200735
Twist Cell lines Yang et al. 200734
SIP1, ZEB2, Hh Human tissues, cell lines Ohta et al. 200938
Nine EMT related proteins Human tissues Kim et al. 200932
Snail, Slug, vimentin Cell lines, H. pylori Yin et al. 201037
Colorectal carcinoma
E-cadherin Human tissues Wheeler et al. 200139
Snail Human tissues Roy et al. 200540
Slug Human tissues, cell lines Shioiri et al. 200641
ZEB1 Human tissues, cell lines Spaderna et al. 200644
Slug Human tissues Hong et al. 200842
Snail, COX-2 Human tissues, cell lines Jang et al. 200943
Hepatocellular carcinoma
Snail Cell lines, animal Jiao et al. 200246
Snail Human tissues, cell lines, animal Sugimachi et al. 200347
Snail, SIP1, MMP Cell lines Miyoshi et al. 200448
Twist Human tissues, cell lines Lee et al. 200649
TGF-β, TGF-β receptor kinase inhibitor Human tissues, cell lines Fransvea et al. 200851
Snail, Twist Human tissues, cell lines, animal Yang et al. 200945
TGF-β, Smad3, HCV-core protein Human tissues, cell lines, animal Battaglia et al. 200950
Pancreatic carcinoma
Snail, Slug, and Twist Human tissues, cell lines Hotz et al. 200755
Twist Human tissues, pancreatic juice, cell lines Ohuchida et al. 200757
SIP1, collagen type I Human tissues, cell lines Imamichi et al. 200756
E-cadherin, β-catenin Cell lines Shah et al. 200759
Twist, Slug Human tissues Cates et al. 200958
Vimentin, ZEB1, Slug, Snail, NF-κ B, Notch-2, Jagged-1 Cell lines Wang et al. 200960

  EMT, epithelial-mesenchymal transition; Hh, hedgehog; ZEB, zinc finger E-box homeobox; MMP, matrix metalloproteinase; NF-κ B, nuclear factor-κ B; SIP, smad interacting protein; cox-2, cycloxygenase-2.

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