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CDCP1 enhances Wnt signaling in colorectal cancer promoting nuclear localization of β-catenin and E-cadherin.
- Source :
-
Oncogene [Oncogene] 2020 Jan; Vol. 39 (1), pp. 219-233. Date of Electronic Publication: 2019 Aug 30. - Publication Year :
- 2020
-
Abstract
- Elevated CUB-domain containing protein 1 (CDCP1) is predictive of colorectal cancer (CRC) recurrence and poor patient survival. While CDCP1 expression identifies stem cell populations that mediate lung metastasis, mechanisms underlying the role of this cell surface receptor in CRC have not been defined. We sought to identify CDCP1 regulated processes in CRC using stem cell populations, enriched from primary cells and cell lines, in extensive in vitro and in vivo assays. These experiments, demonstrating that CDCP1 is functionally important in CRC tumor initiation, growth and metastasis, identified CDCP1 as a positive regulator of Wnt signaling. Detailed cell fractionation, immunoprecipitation, microscopy, and immunohistochemical analyses demonstrated that CDCP1 promotes translocation of the key regulators of Wnt signaling, β-catenin, and E-cadherin, to the nucleus. Of functional importance, disruption of CDCP1 reduces nuclear localized, chromatin-associated β-catenin and nuclear localized E-cadherin, increases sequestration of these proteins in cell membranes, disrupts regulation of CRC promoting genes, and reduces CRC tumor burden. Thus, disruption of CDCP1 perturbs pro-cancerous Wnt signaling including nuclear localization of β-catenin and E-cadherin.
- Subjects :
- Active Transport, Cell Nucleus genetics
Carcinogenesis genetics
Cell Proliferation genetics
Colorectal Neoplasms pathology
Epithelial-Mesenchymal Transition genetics
Gene Expression Regulation, Neoplastic genetics
HCT116 Cells
Humans
Neoplasm Recurrence, Local genetics
Neoplasm Recurrence, Local pathology
Wnt Signaling Pathway genetics
Antigens, Neoplasm genetics
Cadherins genetics
Cell Adhesion Molecules genetics
Colorectal Neoplasms genetics
beta Catenin genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5594
- Volume :
- 39
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 31471585
- Full Text :
- https://doi.org/10.1038/s41388-019-0983-3