Slug overexpression induces stemness and promotes hepatocellular carcinoma cell invasion and metastasis

Abstract

Detection of metastasis of hepatocellular carcinoma (HCC) is crucial for early diagnosis. Epithelial-mesenchymal transition (EMT) is a common event in the metastasis of tumor cells. Slug and Snail are homologous proteins, which play an important role in EMT. The present study aimed to investigate whether Slug and Snail overexpression is associated with the invasiveness of HCC in vitro and in vivo. Invasion, colony formation and wound healing assays, as well as flow cytometry analysis, were performed to examine the invasiveness and proliferation capabilities of HepG2 cells following transfection with cNDA or the siRNA of Slug or Snail. The effects of Slug on HCC in vivo were examined using a xenograft model. Slug upregulation increased the percentage of cluster of differentiation (CD)133+ cells among HepG2 cells, and induced cell invasion and proliferation; whereas Snail upregulation did not affect the cells in vitro. The Slug overexpression group exhibited the highest rate of tumor growth compared with the Snail overexpression and control groups in vivo. These findings demonstrated that Slug increases the percentage of CD133+ cells, promotes the clonigenicity of HCC cells and induces a stronger stemness in Slug-overexpressing cells. These changes activate dormant developmental pathways in invading tumor cells. Thus, Slug may serve as a novel target for HCC prognosis and therapy.

Epithelial-to-mesenchymal plasticity of cancer stem cells: therapeutic targets in hepatocellular carcinoma

“…Overexpression of Slug but not Snail has been reported in the HCC cell line, HepG2, to induce EMT and enhance CSC marker CD133 [69]. The EMT-CSC link may also be exploited to enrich for CSCs.…”

Severe Hepatitis Promotes Hepatocellular Carcinoma Recurrence via NF-κB Pathway-Mediated Epithelial–Mesenchymal Transition after Resection

“…Several EMT regulators, including of Twist (20, 21), Snail (21, 22), Slug (23, 24), Zeb1/2 (25, 26), β-catenin (27), FoxC1/2 (28) and Sox4 (29) are known to induce EMT in HCC cells, and their expression levels also correlate with patient survival. To further delineate the importance of these EMT regulators in HCC, we profiled their gene expression using the CCLE database and found that Twist, Snail, Slug, Zeb1/2 and β-catenin were upregulated in mesenchymal-type but downregulated in epithelial-type HCC cells (Supplementary Fig.…”

E‐cadherin‐Fc chimera protein matrix enhances cancer stem‐like properties and induces mesenchymal features in colon cancer cells

“…Cumulative evidence further emphasizes the links between EMT and CSC including their similar characteristics, such as tumorigenesis, enhanced survival signals, and metastatic ability. Mesenchymal markers including ZEB1, Snail1, and Slug are thought to be involved in CSC maintenance and tumorigenesis . SOX9 is stabilized through combination with the transcription factor Slug, promoting CSC properties and metastasis .…”