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A novel RIP1-mediated canonical WNT signaling pathway that promotes colorectal cancer metastasis via β -catenin stabilization-induced EMT.
- Source :
-
Cancer gene therapy [Cancer Gene Ther] 2023 Oct; Vol. 30 (10), pp. 1403-1413. Date of Electronic Publication: 2023 Jul 27. - Publication Year :
- 2023
-
Abstract
- RIP1 (receptor-interacting protein kinase 1) is an important component of TNF-α signaling that contributes to various pathological effects. Here, we revealed new potential roles of RIP1 in controlling WNT/β-catenin canonical signaling to enhance metastasis of colorectal cancer (CRC). First, we showed that WNT3A treatment sequentially increased the expression of RIP1 and β-catenin. Immunohistochemical analyses of human CRC tissue arrays consisting of normal, primary, and metastatic cancers indicated that elevated RIP1 expression might be related to β-catenin expression, carcinogenesis, and metastasis. Intravenous injection of RIP1 over-expressed CRC cells into mice has demonstrated that RIP1 may promote metastasis. Immunoprecipitation (IP) results indicated that WNT3A treatment induces direct binding between RIP1 and β-catenin, and that this stabilizes the β-catenin protein in a manner that depends on the regulation of RIP1 ubiquitination via downregulation of the E3 ligase, cIAP1/2. Elimination of cIAP1/2 expression and inhibition of its ubiquitinase activity enhance WNT3A-induced RIP1 and β-catenin protein expression and binding, which stimulates endothelial-mesenchymal transition (EMT) induction to enhance the migration and invasion of CRC cells in vitro. The results of the in vitro binding assay and IP of exogenous RIP1-containing CRC cells additionally verified the direct binding of RIP1 and β-catenin. RIP1 expression can destroy the β-catenin-β-TrCP complex. Taken together, these results suggest a novel EMT-enhancing role of RIP1 in the WNT pathway and suggest a new canonical WNT3A-RIP1-β-catenin pathway that contributes to CRC malignancy by promoting EMT.<br /> (© 2023. The Author(s).)
Details
- Language :
- English
- ISSN :
- 1476-5500
- Volume :
- 30
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Cancer gene therapy
- Publication Type :
- Academic Journal
- Accession number :
- 37500894
- Full Text :
- https://doi.org/10.1038/s41417-023-00647-6