Prickle-1 negatively regulates Wnt/beta-catenin pathway by promoting Dishevelled ubiquitination/degradation in liver cancer.
OBJECTIVE
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.
Chan
David W
DW
Department of Pathology, S H Ho Foundation Research Laboratories and Hong Kong Jockey Club Clinical Research Centre, Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong.
Chan
Chung-Yiu
CY
Yam
Judy W P
JW
Ching
Yick-Pang
YP
Ng
Irene O L
IO
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D016384:Consensus Sequence; D000072261:Dishevelled Proteins; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007668:Kidney / Q000166:cytology; D060588:LIM Domain Proteins; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C000606584:DVL3 protein, human; D000072261:Dishevelled Proteins; D060588:LIM Domain Proteins; C515173:PRICKLE1 protein, human; D010750:Phosphoproteins; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D051153:Wnt Proteins; D051176:beta Catenin