A novel RIP1-mediated canonical WNT signaling pathway that promotes colorectal cancer metastasis via β -catenin stabilization-induced EMT

• Published in: Cancer gene therapy Vol. 30; no. 10; pp. 1403 - 1413
• Main Authors: Kang, A-Ram, Kim, Jung-Lim, Kim, YoungHa, Kang, Sanghee, Oh, Sang-Cheul, Park, Jong Kuk
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2023; Nature Publishing Group
• Subjects: 13/95; 14; 14/105; 14/63; 38; 42; 42/89; 631/67/327; 64; 692/699/67/327; 82; 82/51; 82/80; 96; 96/1; Biomedical and Life Sciences; Biomedicine; Carcinogenesis; Colorectal cancer; Colorectal carcinoma; Down-regulation; Gene Expression; Gene Therapy; Immunoprecipitation; Kinases; Malignancy; Metastases; Metastasis; Proteins; Signal transduction; Tumor necrosis factor-α; Ubiquitin-protein ligase; Ubiquitination; Wnt protein; β-Catenin
• ISSN: 0929-1903; 1476-5500
• DOI: 10.1038/s41417-023-00647-6

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.