The Role of Epithelial-mesenchymal Transition in the Gastroenterology

Sung Moo Kim; Joung-Ho Han; Seon Mee Park

doi:10.4166/kjg.2010.56.2.69

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

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Korean J Gastroenterol 2010;56(2):69-77.

Published online: 21 February 2010

DOI: https://doi.org/10.4166/kjg.2010.56.2.69

The Role of Epithelial-mesenchymal Transition in the Gastroenterology

Sung Moo Kim, M.D., Joung-Ho Han, M.D., Seon Mee Park, M.D.

Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju, Korea

Correspondence to: Seon Mee Park, M.D. Department of Internal Medicine, Chungbuk National University College of Medicine, 410, Seongbong-ro, Heungdeok- gu, Cheongju 361-711, Korea Tel: +82-43-269-6019, Fax: +82-43-273-3252 E-mail: smpark@chungbuk.ac.kr

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.

Keywords: Epithelial-mesenchymal transition, Gastrointestinal cancer, Hepatic fibrosis

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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.

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).

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).

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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