Epithelial-to-mesenchymal Transition Leads to the Acquisition of Cancer Stem Cell Characteristics in Liver Cancer

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Introduction: Cancer Stem Cells (CSCs) account for chemotherapy resistance and metastasis. Epithelial-to-mesenchymal transition (EMT) of hepatocellular carcinoma (HCC) results in tumor progression and invasive/metastatic cells. Weinberg proposes that breast cancer cells acquire CSCs characteristics after EMT. Our goal is to understand the role of the transcriptional repressor Snail in driving EMT and inducing a CSC phenotype within HCC. Results: Within murine models and human HCC lines, a mesenchymal phenotype is associated with a significant increase in stem cell expression profile (Oct4, Nanog, Bmi1), suppressed hepatocyte differentiation markers, and up-regulated EMT expression profile, including Snail. Mesenchymal HCC cells demonstrate increased resistance to chemotherapy and ligand mediated apoptosis, increased spheroid formation, and increased metastatic potential in-vivo. Dynamic Network Modeling provides in-silico support for Snail as the critical node within the vast EMT network to maintain a mesenchymal phenotype. Snail down-regulation reverses EMT and results in down-regulation of CSC gene expression and reversal of CSC characteristics. Down-regulation of other EMT drivers, such as Zeb1, does not reverse metastatic potential in-vivo. Conclusion: In liver cancer, Snail represents a critical node within the EMT pathway for maintaining a metastatic phenotype, and Snail up-regulation is associated with the acquisition of CSC characteristics.