Notch3 functions as a regulator of cell self-renewal by interacting with the β-catenin pathway in hepatocellular carcinoma

Abstract

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.

Diosmetin triggers cell apoptosis by activation of the p53/Bcl-2 pathway and inactivation of the Notch3/NF-κB pathway in HepG2 cells

“…Notch3 was identified as a positive marker associated with aggressive traits and short survival in HCC, since patients with high levels of Notch3 expression commonly had a poor prognosis (13). The present authors also reported that Notch3 expression is inversely correlated with beta-catenin content but positively associated with the protein level of Nanog, thus confirming that Notch3 serves a role in modulating the stemness of tumor cells via the inactivation of the Wnt/beta-catenin pathway (14). Patients with high Notch1 or Notch3 expression were at a significantly increased risk for shortened survival time (15).…”

Highly Tumorigenic Diffuse Large B Cell Lymphoma Cells Are Produced by Coculture with Stromal Cells

“…As potent tumorigenic potential is one of the most important properties of cancer stem cells [48], these suspended lymphoma cells can be regarded as cancer stem-like cells. Notch activation has been found to correlate with cancer stem cell characteristics [49-51]. Our findings also confirm that inhibition of Notch signaling by DAPT can abolish the emergence of highly tumorigenic lymphoma cells.…”

Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis

“…While it is possible that a decrease or disruption of Wnt/β-catenin signaling further enhanced HCC in TKOβcat mice through another mechanism(s) that is yet to be defined, the important clinical findings reported by Fitamant et al that signatures of β-catenin activation and YAP activation are mutually exclusive in HCC human patients (80) strongly suggest that it is unlikely that Wnt/β-catenin activation contributed to the development of HCC development in Hippo-DKO mice. In contrast, YAP and Notch activation signatures are highly correlated in HCC (80,81), arguing for the clinical importance of the Notch and YAP/TAZ positive feedback loop we identified in this study. Therefore, inhibition of this positive feedback loop by Wnt/β-catenin is at least one of the underlying mechanisms whereby HCC development in DKO mice was further enhanced upon β-catenin removal.…”