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.
Highlights
Hepatocellular carcinoma (HCC) is the third most common cancer worldwide, and over fifty percent of the cases are found in Asia [1]
Notch3 expression is activated in hepatocellular carcinoma (HCC) tumor tissues
Cancer stem cells (CSCs), called tumor-initiating cells (T-ICs), are a highly heterogeneous tumor progenitor cell population that in several carcinomas is involved in the processes of disease progression, including tumor initiation, invasion, metastasis, chemotherapeutic resistance and tumor recurrence [16]
Summary
Hepatocellular carcinoma (HCC) is the third most common cancer worldwide, and over fifty percent of the cases are found in Asia [1]. Even when surgical resection is combined with the chemotherapeutic management of HCC, this treatment can still be unsatisfactory due to the recurrence and metastasis of malignant cancer cells. Recent evidence suggests that the presence and metastasis of CSCs results in unsatisfactory chemotherapeutic outcomes and poor prognoses [4, 5]. The discovery of aberrant Notch gene translocation in human pre-T-cell acute lymphoblastic leukemia (T-ALL) was one of the first indications that the Notch pathway is linked to human cancer pathogenesis [9, 10]. Many studies have proposed that Notch signaling is involved in maintaining the stemness of CSCs. other previous studies indicated that the Notch pathway functions as a tumor suppressor in carcinogenesis [11, 14, 15]
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