Metastatic ability and the epithelial-mesenchymal transition in induced cancer stem-like hepatoma cells

Summary

Cancer stem cells (CSCs) are thought to play important roles in cancer malignancy. Previously, we successfully induced sphere cancer stem-like cells (CSLCs) from several cell lines and observed the property of chemoresistance. In the present study, we examined the metastatic potential of these induced CSLCs. CSLCs were induced from a human hepatoma cell line (SK-HEP-1) in a unique medium containing neural survival factor-1. Splenic injection of cells into immune-deficient mice was used to assess hematogenous liver metastasis. Transcriptomic strand-specific RNA-sequencing analysis, the quantitative real-time polymerase chain reaction, and flow cytometry were performed to examine the expression of epithelial-mesenchymal transition (EMT)-related genes. Splenic injection of CSLCs resulted in a significantly increased frequency of liver metastasis compared to parental cancer cells (P < 0.05). In CSLCs, a mesenchymal marker, Vimentin, and EMT-promoting transcription factors, Snail and Twist1, were up-regulated compared to parental cells. Correspondingly, significant enrichment of the molecular signature of the EMT in CSLCs relative to parental cancer cells was shown (q < 0.01) by RNA-sequencing analysis. This analysis also revealed differential expression of CD44 isoforms between CSLCs and parental cancer cells. Increasing CD44 isoforms containing an extra exon were observed, while the standard CD44 isoform decreased in CSLCs compared to parental cells. Interestingly, another CD44 variant isoform encoding a short cytoplasmic tail was also up-regulated in CSLCs (11.7-fold). Our induced CSLCs possess an increased liver metastatic potential in which promotion of the EMT and up-regulation of CD44 variant isoforms, especially short-tail, were observed.

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