Abstract
Human hepatocellular carcinoma (HCC) is driven and maintained by liver cancer stem cells (LCSCs) that display stem cell properties. These LCSCs are promoted by the intersecting of Notch and Wnt/β-Catenin signaling pathways. In this study, we demonstrate that LCSCs with markers CD90, CD24, CD13, and CD133 possess stem properties of self-renewal and tumorigenicity in NOD/SCID mice. The increased expression of these markers was correlated with advanced disease stage, larger tumors, and worse overall survival in 61 HCC cases. We also found that both Notch and Wnt/β-catenin signaling pathways played important roles in increasing the stem-ness characteristics of LCSCs. Our data suggested that Notch1 was downstream of Wnt/β-catenin. The active form of Notch1 intracellular domain (NICD) expression depended on Wnt/β-catenin pathway activation. Moreover, Notch1 negatively contributed to Wnt/β-catenin signaling modulation. Knock down of Notch1 with lentivirus N1ShRNA up-regulated the active form of β-catenin. Ectopic expression of NICD with LV-Notch1 in LCSCs attenuated β-catenin/TCF dependent luciferase activity significantly. In addition, there was a non-proteasome mediated feedback loop between Notch1 and Wnt/β-catenin signaling in LCSCs. The central role of Notch and the Wnt/β-catenin signaling pathway in LCSCs may provide an attractive therapeutic strategy against HCC.
Highlights
Human hepatocellular carcinoma (HCC) is currently the fifth most common cancer and third leading cause of cancer death worldwide [1]
We found that Notch and Wnt/β-catenin signaling pathways play a crucial role in maintaining the self-renewal of CD90, CD24, CD13, CD133 high expressed sphere-forming liver cancer stem cells (LCSCs)
To investigate whether cancer stem cell markers were over-expressed in HCC specimens, we retrospectively evaluated the expression levels of five cancer stem cell markers (CD90, CD44, CD133, CD13 and CD24) using IHC in 61 matched human HCC specimens and adjacent liver specimens
Summary
Human hepatocellular carcinoma (HCC) is currently the fifth most common cancer and third leading cause of cancer death worldwide [1]. Various stem cell markers are essential for identifying LCSCs. Previous studies have demonstrated that cluster of differentiation CD133 [6], CD90 [7], CD13 [8], CD24 [9], CD44 [10] and Epithelial cell adhesion molecule (EpCAM) [11] are cell surface markers for LCSCs. A multiple markers hypothesis has been suggested for CSCs in breast, pancreatic cancers and HCC [12, 13]. Yang et al demonstrated that the CD90+CD44+ phenotype of liver CSCs may explain the aggressive growth pattern of HCC [7]. It remains unclear whether HCC patients with these markers share similar or distinct features, and whether combined detection of those markers would be more significant in predicting the prognosis of clinic-pathological characteristics in patients
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