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Biochem Biophys Res Commun. 2016 Sep 2;477(4):568-574. doi: 10.1016/j.bbrc.2016.06.077. Epub 2016 Jun 16.

Synergistic effects of CD44 and TGF-β1 through AKT/GSK-3β/β-catenin signaling during epithelial-mesenchymal transition in liver cancer cells.

Author information

1
The Catholic University Liver Research Center & WHO Collaborating Center of Viral Hepatitis, The Catholic University of Korea, Seoul, Republic of Korea.
2
The Catholic University Liver Research Center & WHO Collaborating Center of Viral Hepatitis, The Catholic University of Korea, Seoul, Republic of Korea; Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address: garden@catholic.ac.kr.
3
The Catholic University Liver Research Center & WHO Collaborating Center of Viral Hepatitis, The Catholic University of Korea, Seoul, Republic of Korea; Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address: baesh@catholic.ac.kr.
4
The Catholic University Liver Research Center & WHO Collaborating Center of Viral Hepatitis, The Catholic University of Korea, Seoul, Republic of Korea; Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea.

Abstract

Cancer metastasis is strongly correlated with epithelial-mesenchymal transition (EMT), in which transforming growth factor-β (TGF-β) signaling plays a central role. CD44 has emerged as a cancer stem cell (CSC) marker that strongly induces EMT together with TGF-β1. This study aimed to investigate the link between high CD44 and TGF-β1 levels during EMT in HCC cell lines. FACS analysis showed high expression of CD44 in TGF-β1-positive SNU-368 cells and TGF-β1-negative SNU-354 cells. SNU-368 CD44(+) cells showed EMT through up-regulation of the AKT/GSK-3β/β-catenin pathway. By comparison, SNU-354 CD44(+) cells showed only increased N-cadherin expression, which was not accompanied by a decrease in E-cadherin expression, and also down-regulated the AKT/GSK-3β/β-catenin pathway. However, TGF-β1-stimulated SNU-354 cells (CD44/TGF-β1(+)) exhibited lower E-cadherin and higher N-cadherin expression with increased AKT/GSK-3β/β-catenin pathway activity. CD44/TGF-β1(+) SNU-354 cells also showed enhanced migration and formed larger spheres, while the TGF-β1-induced stem cell properties returned to their original state with the TGF-β1 inhibitor SB431542. SB431542-treated SNU-368 (CD44/TGF-β1(-)) cells also showed diminished N-cadherin and AKT/GSK-3β/β-catenin pathway activity and further decreased cell motility in a wound healing assay. However, CD44 knockdown in SNU-354 cells did not induce EMT even after treatment with TGF-β1. Finally, double inhibition of both CD44 and TGF-β1 further decreased migration and sphere formation more strongly than a single inhibition in SNU-368 cells. In conclusion, the current study demonstrated the synergistic interactions between CD44 and TGF-β1 in EMT induction and CSC properties through the AKT/GSK-3β/β-catenin pathway in HCC cells.

KEYWORDS:

CD44; Epithelial-mesenchymal transition (EMT); Hepatocellular carcinoma (HCC); Metastasis; Transforming growth factor-β1 (TGF-β1)

PMID:
27320862
DOI:
10.1016/j.bbrc.2016.06.077
[Indexed for MEDLINE]

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