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Wnt1 inducible signaling pathway protein-1 (WISP1) may play an important role in promoting carcinogenesis. However, the biological function and underlying mechanism of WISP1 in pancreatic carcinogenesis still remains enigmatic. In this study, immunochemistry staining showed that protein levels of WISP1 were more significantly upregulated in pancreatic ductal adenocarcinoma (PDAC) tissues with  Tp53  mutation than in PDAC tissues with  Tp53  wild-type. In addition, a significant correlation was observed between increased malignant phenotype of tumors from well-differentiated adenocarcinoma tissues to moderately- or poorly-differentiated adenocarcinoma tissues shifting from cytoplasmic expression to nuclear accumulation of WISP1. Interestingly,  WISP1  expression was correlated with the poor prognosis in PDAC patients with  Tp53  mutation. Also, the biological function analysis showed that  WISP1  may act as a potential oncogene in PDAC cells. In addition, immunofluorescence analysis showed that  Tp53  mutation promoted  WISP1  expression in PanIN and PDAC cells, while Siah E3 Ubiquitin Protein Ligase 1 ( Siah1 ) inhibited  WISP1  expression in PDAC cells. Moreover, through immunoprecipitation, immunoblotting analysis,  in vitro  binding assay, and ubiquitination assay, we found that  Tp53  mutation inhibited ubiquitination and degradation of Siah1-dependent WISP1. Therefore,  Tp53  mutation-Siah1-WISP1 is a new signaling pathway, playing an important role in pancreatic carcinogenesis.

Tp53 Mutation Inhibits Ubiquitination and Degradation of WISP1 via Down-Regulation of Siah1 in Pancreatic Carcinogenesis