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  • Title: Prickle-1 negatively regulates Wnt/beta-catenin pathway by promoting Dishevelled ubiquitination/degradation in liver cancer.
    Author: Chan DW, Chan CY, Yam JW, Ching YP, Ng IO.
    Journal: Gastroenterology; 2006 Oct; 131(4):1218-27. PubMed ID: 17030191.
    Abstract:
    BACKGROUND & AIMS: Aberrant activation of Wnt signaling due to accumulation of beta-catenin has been linked to tumorigenesis. Mutations of beta-catenin, APC, and axins are important but not frequent enough to be accountable for the accumulation of beta-catenin in human hepatocellular carcinoma (HCC). In this study, we characterized the roles of Prickle-1, a Dishevelled (Dvl)-associated protein, in regulation of Wnt/beta-catenin activity in HCC. METHODS: The expression levels of human Prickle-1 and Dvl3 were examined in HCC cell lines and human HCC samples. The interaction and effects of Prickle-1 on Dvl3, the Wnt/beta-catenin pathway, and cell growth were assessed in HCC cell lines. RESULTS: We showed that Prickle-1 bound with Dvl3 and facilitated Dvl3 ubiquitination/degradation, and this was through its destruction box (D-box) motifs. Enforced expression of Prickle-1 significantly reduced the Wnt/beta-catenin activity and tumorigenic properties of HCC cells. Clinicopathologic analysis showed that underexpression of Prickle-1 was significantly associated with overexpression of Dvl3, beta-catenin accumulation (P = .023), and larger tumor size (P = .030). CONCLUSIONS: Our results have elucidated a novel mechanistic relationship between Prickle-1 and Dvl3 in the Wnt/beta-catenin pathway. The facilitation of Prickle-1 on Dvl3 degradation and the suppression of beta-catenin activity and cell growth suggest that Prickle-1 is a negative regulator of the Wnt/beta-catenin signaling pathway and is a putative tumor suppressor in human HCCs.
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