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

• Published in: Oncogene Vol. 32; no. 41; pp. 4873 - 4882
• Main Authors: Suh, Y, Yoon, C-H, Kim, R-K, Lim, E-J, Oh, Y S, Hwang, S-G, An, S, Yoon, G, Gye, M C, Yi, J-M, Kim, M-J, Lee, S-J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10-10-2013; Nature Publishing Group
• Subjects: 631/67/395; 631/80/84/2176; 631/80/86; 692/699/67/1504/1610; Apoptosis; Cancer invasiveness; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell activation; Cell adhesion; Cell Biology; Cell Line, Tumor; Claudin-1 - metabolism; E-cadherin; Epithelial-Mesenchymal Transition; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Growth; Hepatocellular carcinoma; Hepatocytes; Homeodomain Proteins - metabolism; Human Genetics; Humans; Integral membrane proteins; Internal Medicine; Liver - metabolism; Liver - pathology; Liver cancer; Liver cells; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Medicine; Medicine & Public Health; Mesenchyme; Metastases; Motility; N-Cadherin; Neoplasm Invasiveness; Oncology; original-article; Pathogenesis; Phenotypes; Polarity; Proto-Oncogene Proteins c-abl - metabolism; Proto-Oncogene Proteins c-raf - metabolism; Raf protein; ras Proteins - metabolism; Signal Transduction; Snail Family Transcription Factors; Tight junctions; Tight Junctions - metabolism; Transcription factors; Transcription Factors - metabolism; Vimentin; Zinc Finger E-box-Binding Homeobox 1; β-Catenin; ERK signaling; epithelial–mesenchymal transition; Claudin-1
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2012.505

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.