Notch3 functions as a regulator of cell self-renewal by interacting with the β-catenin pathway in hepatocellular carcinoma
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Qingyu Zhang1,*, Caijie Lu1,*, Tao Fang1, Yongcun Wang2, Wenhua Hu3, Jie Qiao1, Bin Liu1, Jie Liu1, Nianping Chen1, Mingyi Li1, Runzhi Zhu1
1Laboratory of Hepatobiliary Surgery of Affiliated Hospital of Guangdong Medical College, Zhanjiang Key Laboratory of Hepatobiliary Diseases, Zhanjiang 524001, China
2Oncology Center, Affiliated Hospital of Guangdong Medical College, Zhanjiang 524001, China
3Department of Pathology, Affiliated Hospital of Guangdong Medical College, Zhanjiang 524001, China
*These authors contributed equally to this work
Mingyi Li, e-mail: [email protected]
Nianping Chen, e-mail: [email protected]
Runzhi Zhu, e-mail: [email protected]
Keywords: Notch3, Beta-catenin, cancer stem cells, hepatocellular carcinoma
Received: August 07, 2014 Accepted: December 11, 2014 Published: January 21, 2015
The Notch signaling pathway plays a role in cell proliferation, differentiation. Emerging data have revealed aberrant Notch3 expression in hepatocellular carcinoma (HCC). However, whether Notch3 plays a role in tumorigenesis or tumor progression is unclear. In this study, we found that over 71.8% of the cases studied had high Notch3 expression levels (n = 32); Notch3 expression positively correlated with alpha-fetoprotein (AFP) levels (p = 0.0311) and negatively correlated with the differentiation grade (p = 0.042). We demonstrated that the patients with higher levels of Notch3 expression commonly had a poor prognosis. We discovered that Notch3 expression is inversely correlated with β-catenin content but positively associated with the protein level of Nanog. In parallel, we found that Notch3 attenuation resulted in the upregulation of β-catenin and the downregulation of Nanog in the hepatoma cell lines QGY7701 and HepG2. The downregulation of Notch3 enhanced the sensitivity to cisplatin in the QGY7701 and HepG2 cells and inhibited the ability of QGY7701 cells to form tumors. The Notch3-positive cells had higher levels of aldehyde dehydrogenase (ALDH) activity, and a tendency to differentiate into Notch3-negative cells. In conclusion, our study demonstrated that Notch3 plays a role in modulating the stemness of tumor cells via the inactivation of the Wnt/β-catenin pathway.
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