SOSTDC1 promotes invasion and liver metastasis in colorectal cancer via interaction with ALCAM/CD166.
The mechanistic basis of liver metastasis in colorectal cancer remains poorly understood. We previously reported that the sclerostin domain containing-1 (SOSTDC1) protein is overexpressed in the secretome of metastatic colorectal cancer cells and can inhibit liver homing. Here, we investigated the mechanisms of SOSTDC1 for promoting invasiveness and progression of ... colorectal cancer liver metastasis. SOSTDC1 inhibition of BMP4 maintains the expression of cancer stem cell traits, including SOX2 and NANOG. Immunoprecipitation and mass spectrometry analyses reveal the association of SOSTDC1 with ALCAM/CD166, which was confirmed by confocal microscopy and competition ELISA. Interaction with ALCAM is mediated by the N-terminal region of SOSTDC1, which contains a sequence similar to the ALCAM-binding motif used by CD6. Knocking down either SOSTDC1 or ALCAM expression, or using blocking antibodies, reduces the invasive activity by inhibiting Src and PI3K/AKT signaling pathways. In addition, ALCAM interacts with the ?2ss1 and ?1ss1 integrins, providing a possible link to Src activation. Finally, inoculation of SOSTDC1-silenced metastatic cells increases mouse survival by inhibiting liver metastasis. In conclusion, SOSTDC1 promotes invasion and liver metastasis in colorectal cancer, by overcoming BMP4-specific antimetastatic signals and inducing ALCAM-mediated Src and PI3K/AKT activation. These experiments underscore the potential of SOSTDC1 as a therapeutic target in metastatic colorectal cancer.
Mesh Terms:
Actins, Adaptor Proteins, Signal Transducing, Animals, Antigens, CD, Biomarkers, Tumor, Cell Adhesion Molecules, Neuronal, Colorectal Neoplasms, Disease Models, Animal, Fetal Proteins, Gene Expression, Humans, Immunohistochemistry, Liver Neoplasms, Mice, Models, Biological, Neoplasm Invasiveness, Phosphatidylinositol 3-Kinases, Protein Binding, Protein Multimerization, Proto-Oncogene Proteins c-akt, Signal Transduction, src-Family Kinases
Actins, Adaptor Proteins, Signal Transducing, Animals, Antigens, CD, Biomarkers, Tumor, Cell Adhesion Molecules, Neuronal, Colorectal Neoplasms, Disease Models, Animal, Fetal Proteins, Gene Expression, Humans, Immunohistochemistry, Liver Neoplasms, Mice, Models, Biological, Neoplasm Invasiveness, Phosphatidylinositol 3-Kinases, Protein Binding, Protein Multimerization, Proto-Oncogene Proteins c-akt, Signal Transduction, src-Family Kinases
Oncogene
Date: Dec. 01, 2019
PubMed ID: 32801337
View in: Pubmed Google Scholar
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