Abstract
Liver cancer stem cells (CSCs) are resistant to conventional chemotherapy and radiation, which may destroy tumor masses, but not all liver CSCs contribute to tumor initiation, metastasis, and relapse. In the present study, we showed that liver CSCs with elevated Wnt/β-catenin signaling possess much greater self-renewal and clonogenic potential. We further documented that the increased clonogenic potential of liver CSCs is highly associated with changes in Wnt/β-catenin signaling and that Wnt/β-catenin signaling activity is positively correlated with CD133 expression and aldehyde dehydrogenase (ALDH) enzymatic activity. Notably, the small molecule inhibitor CWP232228, which antagonizes the binding of β-catenin to TCF in the nucleus, inhibits Wnt/β-catenin signaling and depletes CD133+/ALDH+ liver CSCs, thus ultimately diminishing the self-renewal capacity of CSCs and decreasing tumorigenicity in vitro and in vivo. Taken together, our findings suggest that CWP232228 acts as a candidate therapeutic agent for liver cancer by preferentially targeting liver CSCs.
Highlights
Hepatocellular carcinoma (HCC, called malignant hepatoma), the most common type of liver cancer, is the fifth most frequently diagnosed solid tumor and the third leading cause of cancer death in the world [1, 2]
Recent evidence has revealed the regulatory role of Wnt/β‐catenin signaling in maintaining liver cancer stem cells (CSCs) [18, 30]
We propose that Wnt/β‐catenin signaling might play a critical role in the self‐renewal and tumorigenic capacities of liver CSCs
Summary
Hepatocellular carcinoma (HCC, called malignant hepatoma), the most common type of liver cancer, is the fifth most frequently diagnosed solid tumor and the third leading cause of cancer death in the world [1, 2]. Wnt/β‐catenin [3], MAPK/ERK1/2 [4], PI3K/Akt [5], IGF‐I [6], and VEGF [7] signaling pathways Among these activated signaling pathways, Wnt/β‐catenin signaling plays crucial roles in the development of HCC [8] and is generally regarded as one of the most difficult pathways to inhibit [9]. Liver CSCs are resistant to conventional anticancer therapies such as chemotherapy [16] and radiotherapy [17] In this context, novel compounds and therapeutic strategies that focus on the selective targeting of liver CSCs will improve liver cancer patient outcomes and survival. The dysfunction of the Wnt/β‐catenin signaling pathway is associated with multiple types of human cancers, including breast [20], colon [21], and ovarian [22]. Few therapeutic agents targeting Wnt/β‐catenin signaling are currently available or under investigation [24]
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