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Claudin-1 induces epithelial–mesenchymal transition through activation of the c-Abl-ERK signaling pathway in human liver cells

Oncogene volume 32, pages 4873–4882 (2013)Cite this article

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A Corrigendum to this article was published on 14 November 2016

Abstract

Claudins (CLDNs) are a family of integral membrane proteins central to the formation of tight junctions, structures that are involved in paracellular transport and cellular growth and differentiation, and are critical for the maintenance of cellular polarity. Recent studies have provided evidence that CLDNs are aberrantly expressed in diverse types of human cancers, including hepatocellular carcinomas (HCCs). However, little is known about how CLDN expression is involved in cancer progression. In this study, we show that CLDN1 has a causal role in the epithelial–mesenchymal transition (EMT) in human liver cells, and that the c-Abl-Ras-Raf-1-ERK1/2 signaling axis is critical for the induction of malignant progression by CLDN1. Overexpression of CLDN1 induced expression of the EMT-regulating transcription factors Slug and Zeb1, and thereby led to repression of E-cadherin, β-catenin expression, enhanced expression of N-cadherin and Vimentin, a loss of cell adhesion, and increased cell motility in normal liver cells and HCC cells. In line with these findings, inhibition of either c-Abl or ERK clearly attenuated CLDN1-induced EMT, as evidenced by a reversal of N-cadherin and E-cadherin expression patterns, and restored normal motility. Collectively, these results indicate that CLDN1 is necessary for the induction of EMT in human liver cells, and that activation of the c-Abl-Ras-Raf-1-ERK1/2 signaling pathway is required for CLDN1-induced acquisition of the malignant phenotype. The present observations suggest that CLDN1 could be exploited as a biomarker for liver cancer metastasis and might provide a pivotal point for therapeutic intervention in HCC.

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Abbreviations

EMT:

epithelial–mesenchymal transition RNA

PI3K:

phosphoinositide 3-kinase

siRNA:

small interfering.

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Acknowledgements

This work was supported by the National Research Foundation (NRF) and Ministry of Education, Science and Technology (MEST), Korean government, through its National Nuclear Technology Program (2012M2A2A7035878) and Converging Research Center Program Grant (2011K000877) funded by the Ministry of Education, Science and Technology.

Author Contributions: Yongjoon Suh: collection and assembly of data, data analysis and interpretation, paper writing; Chang-Hwan Yoon: collection and assembly of data, data analysis and interpretation; Rae-Kwon Kim: collection of data; Eun-Jung Lim: collection of data; Yeong Seok Oh: collection of data; Sang-Gu Hwang: data analysis and interpretation; Sungkwan An: data analysis and interpretation; Gyesoon Yoon: data analysis and interpretation; Myung Chan Gye: data analysis and interpretation; Joo-Mi Yi: data analysis and interpretation; Min-Jung Kim: collection of data Su-Jae Lee: conception and design, paper writing, data analysis and interpretation, final approval of paper.

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  1. Y Suh and C-H Yoon: These authors are contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea

    Y Suh, C-H Yoon, R-K Kim, E-J Lim & S-J Lee

  2. Department of Life Science, College of Natural Sciences, Hanyang University, Seoul, Korea

    Y S Oh & M C Gye

  3. Division of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences, Seoul, Korea

    S-G Hwang & M-J Kim

  4. Functional Genoproteome Research Centre, Konkuk University, Seoul, Korea

    S An

  5. Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, Korea

    G Yoon

  6. Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan, Korea

    J-M Yi

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Suh, Y., Yoon, CH., Kim, RK. et al. Claudin-1 induces epithelial–mesenchymal transition through activation of the c-Abl-ERK signaling pathway in human liver cells. Oncogene 32, 4873–4882 (2013). https://doi.org/10.1038/onc.2012.505

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