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

Zhang Q, Lu C, Fang T, Wang Y, Hu W, Qiao J, Liu B, Liu J, Chen N, Li M, Zhu R - Oncotarget (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Hepatobiliary Surgery of Affiliated Hospital of Guangdong Medical College, Zhanjiang Key Laboratory of Hepatobiliary Diseases, Zhanjiang 524001, China.

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.

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Notch3 signaling activation is negatively associated with β-catenin in HCC tissuesProtein levels were detected by western blot analysis. Notch3 proteins were obviously abundant in most of the tumor tissues (A and B); Notch3 expression is negatively correlated with β-catenin(C, R2 = 0.519, p < 0.05) and positively correlated with Nanog expression (E, R2 = 0.721, p < 0.05); The Notch3 and β-catenin proteins were detected by immunohistochemistry (D) and western blotting (E, L = liver, T = tumor); The correlation between the Notch3 protein level and the Nanog protein level were performed by Pearson correlation analysis (F, R2 = 0.721, p < 0.0136)
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Figure 3: Notch3 signaling activation is negatively associated with β-catenin in HCC tissuesProtein levels were detected by western blot analysis. Notch3 proteins were obviously abundant in most of the tumor tissues (A and B); Notch3 expression is negatively correlated with β-catenin(C, R2 = 0.519, p < 0.05) and positively correlated with Nanog expression (E, R2 = 0.721, p < 0.05); The Notch3 and β-catenin proteins were detected by immunohistochemistry (D) and western blotting (E, L = liver, T = tumor); The correlation between the Notch3 protein level and the Nanog protein level were performed by Pearson correlation analysis (F, R2 = 0.721, p < 0.0136)

Mentions: β-catenin is implicated in cell-cell adhesion as well as gene transcription. Deregulated β-catenin has been discovered in many types of tumors. The activation of β-catenin promotes tumor proliferation. We questioned whether Notch3 regulates the β-catenin signaling pathway. We determined the Notch3 and β-catenin protein content in the tumor specimens and found Notch3 protein accumulation in the tumor tissues (Figure 3A, 3B); this accumulation was inversely associated with the level of β-catenin (Figure 3C, 3D, 3E). These results suggest that Notch3 might inhibit β-catenin accumulation to modulate tumor cell proliferation. However, previous results have shown that Notch3 expression indicates a poor outcome according to survival analyses. Therefore, we supposed that Notch3 might inhibit β-catenin and result in maintaining the stemness of the tumor cell. We thus detected several stemness-related proteins, including Myc, Oct4 and Nanog. We found that Myc and Oct4 were rarely expressed in the tumor samples. However, a significant amount of Nanog expression was detected in these specimens, which was consistent with the Notch3 expression profile (Figure 3E, 3F). Nanog determines the capacity for cellular self-renewal and proliferation. These data indicated that Notch3 might inhibit β-catenin and increase Nanog to modulate tumor cell differentiation and thereby regulate the CSC population in the pathogenesis of HCC.


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

Zhang Q, Lu C, Fang T, Wang Y, Hu W, Qiao J, Liu B, Liu J, Chen N, Li M, Zhu R - Oncotarget (2015)

Notch3 signaling activation is negatively associated with β-catenin in HCC tissuesProtein levels were detected by western blot analysis. Notch3 proteins were obviously abundant in most of the tumor tissues (A and B); Notch3 expression is negatively correlated with β-catenin(C, R2 = 0.519, p < 0.05) and positively correlated with Nanog expression (E, R2 = 0.721, p < 0.05); The Notch3 and β-catenin proteins were detected by immunohistochemistry (D) and western blotting (E, L = liver, T = tumor); The correlation between the Notch3 protein level and the Nanog protein level were performed by Pearson correlation analysis (F, R2 = 0.721, p < 0.0136)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4414145&req=5

Figure 3: Notch3 signaling activation is negatively associated with β-catenin in HCC tissuesProtein levels were detected by western blot analysis. Notch3 proteins were obviously abundant in most of the tumor tissues (A and B); Notch3 expression is negatively correlated with β-catenin(C, R2 = 0.519, p < 0.05) and positively correlated with Nanog expression (E, R2 = 0.721, p < 0.05); The Notch3 and β-catenin proteins were detected by immunohistochemistry (D) and western blotting (E, L = liver, T = tumor); The correlation between the Notch3 protein level and the Nanog protein level were performed by Pearson correlation analysis (F, R2 = 0.721, p < 0.0136)
Mentions: β-catenin is implicated in cell-cell adhesion as well as gene transcription. Deregulated β-catenin has been discovered in many types of tumors. The activation of β-catenin promotes tumor proliferation. We questioned whether Notch3 regulates the β-catenin signaling pathway. We determined the Notch3 and β-catenin protein content in the tumor specimens and found Notch3 protein accumulation in the tumor tissues (Figure 3A, 3B); this accumulation was inversely associated with the level of β-catenin (Figure 3C, 3D, 3E). These results suggest that Notch3 might inhibit β-catenin accumulation to modulate tumor cell proliferation. However, previous results have shown that Notch3 expression indicates a poor outcome according to survival analyses. Therefore, we supposed that Notch3 might inhibit β-catenin and result in maintaining the stemness of the tumor cell. We thus detected several stemness-related proteins, including Myc, Oct4 and Nanog. We found that Myc and Oct4 were rarely expressed in the tumor samples. However, a significant amount of Nanog expression was detected in these specimens, which was consistent with the Notch3 expression profile (Figure 3E, 3F). Nanog determines the capacity for cellular self-renewal and proliferation. These data indicated that Notch3 might inhibit β-catenin and increase Nanog to modulate tumor cell differentiation and thereby regulate the CSC population in the pathogenesis of HCC.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Hepatobiliary Surgery of Affiliated Hospital of Guangdong Medical College, Zhanjiang Key Laboratory of Hepatobiliary Diseases, Zhanjiang 524001, China.

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.

Show MeSH
Related in: MedlinePlus