The EMT (epithelial–mesenchymal transition) is involved in fibrosis and cancer, and is regulated by different signalling pathways mediated through soluble factors, actin reorganization and transcription factor actions. Because the tetraspan (also called tetraspanin) TM4SF5 (transmembrane 4 L6 family member 5) is highly expressed in hepatocellular carcinoma and induces EMT, understanding how TM4SF5 expression in hepatocytes is regulated is important. We explored the mechanisms that induce TM4SF5 expression and whether impaired signalling pathways for TM4SF5 expression inhibit the acquisition of mesenchymal cell features, using human and mouse normal hepatocytes. We found that TGFβ1 (transforming growth factor β1)-mediated Smad activation caused TM4SF5 expression and EMT, and activation of the EGFR [EGF (epidermal growth factor) receptor] pathway. Inhibition of EGFR activity following TGFβ1 treatment abolished acquisition of EMT, suggesting a link from Smads to EGFR for TM4SF5 expression. Further, TGFβ1-mediated EGFR activation and TM4SF5 expression were abolished by EGFR suppression or extracellular EGF depletion. Smad overexpression mediated EGFR activation and TM4SF5 expression in the absence of serum, and EGFR kinase inactivation or EGF depletion abolished Smad-overexpression-induced TM4SF5 and mesenchymal cell marker expression. Inhibition of Smad, EGFR or TM4SF5 using Smad7 or small compounds also blocked TM4SF5 expression and/or EMT. These results indicate that TGFβ1- and growth factor-mediated signalling activities mediate TM4SF5 expression leading to acquisition of mesenchymal cell features, suggesting that TM4SF5 induction may be involved in the development of liver pathologies.
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Research Article|
April 16 2012
Cross-talk between TGFβ1 and EGFR signalling pathways induces TM4SF5 expression and epithelial–mesenchymal transition
Minkyung Kang;
Minkyung Kang
*Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea
†Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Tumor Microenvironment Global Core Research Center, Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
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Suyong Choi;
Suyong Choi
†Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Tumor Microenvironment Global Core Research Center, Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
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Soo-Jin Jeong;
Soo-Jin Jeong
‡Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea
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Sin-Ae Lee;
Sin-Ae Lee
†Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Tumor Microenvironment Global Core Research Center, Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
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Tae Kyoung Kwak;
Tae Kyoung Kwak
†Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Tumor Microenvironment Global Core Research Center, Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
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Hyeonjung Kim;
Hyeonjung Kim
†Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Tumor Microenvironment Global Core Research Center, Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
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Oisun Jung;
Oisun Jung
§Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul 151-742, Republic of Korea
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Mi-Sook Lee;
Mi-Sook Lee
†Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Tumor Microenvironment Global Core Research Center, Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
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Youra Ko;
Youra Ko
§Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul 151-742, Republic of Korea
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Jihye Ryu;
Jihye Ryu
†Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Tumor Microenvironment Global Core Research Center, Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
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Yoon-Ju Choi;
Yoon-Ju Choi
†Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Tumor Microenvironment Global Core Research Center, Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
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Doyoung Jeong;
Doyoung Jeong
†Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Tumor Microenvironment Global Core Research Center, Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
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Hyo Jeong Lee;
Hyo Jeong Lee
‡Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea
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Sang-Kyu Ye;
Sang-Kyu Ye
*Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea
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Sung-Hoon Kim;
Sung-Hoon Kim
1
‡Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea
1Correspondence may be addressed to either of these authors (email sungkim7@khu.ac.kr or jwl@snu.ac.kr).
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Jung Weon Lee
Jung Weon Lee
1
†Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Tumor Microenvironment Global Core Research Center, Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
§Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul 151-742, Republic of Korea
1Correspondence may be addressed to either of these authors (email sungkim7@khu.ac.kr or jwl@snu.ac.kr).
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Publisher: Portland Press Ltd
Received:
August 31 2011
Revision Received:
January 09 2012
Accepted:
January 31 2012
Accepted Manuscript online:
January 31 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 443 (3): 691–700.
Article history
Received:
August 31 2011
Revision Received:
January 09 2012
Accepted:
January 31 2012
Accepted Manuscript online:
January 31 2012
Citation
Minkyung Kang, Suyong Choi, Soo-Jin Jeong, Sin-Ae Lee, Tae Kyoung Kwak, Hyeonjung Kim, Oisun Jung, Mi-Sook Lee, Youra Ko, Jihye Ryu, Yoon-Ju Choi, Doyoung Jeong, Hyo Jeong Lee, Sang-Kyu Ye, Sung-Hoon Kim, Jung Weon Lee; Cross-talk between TGFβ1 and EGFR signalling pathways induces TM4SF5 expression and epithelial–mesenchymal transition. Biochem J 1 May 2012; 443 (3): 691–700. doi: https://doi.org/10.1042/BJ20111584
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