[Tumor-secreted dentin sialophosphoprotein induces oxaliplatin resistance in colorectal cancer through an integrin αvβ3-dependent pathway].

[OBJECTIVES] To determine whether dentin sialophosphoprotein (DSPP) modulates oxaliplatin efficacy for colorectal cancer (CRC) and explore the underlying integrin αvβ3-dependent mechanism.

[METHODS] Immunohistochemistry was used to compare the expression levels of DSPP between oxaliplatin-sensitive and oxaliplatin-resistant CRC tissues. The changes in oxaliplatin sensitivity in parental and oxaliplatin-resistant CRC cell lines after DSPP knockdown or overexpression were assessed using CCK-8 assay, and Western blotting was used to evaluate the efficacy of DSPP modulation and MAPK pathway activity. The interaction between DSPP and integrin αvβ3 was examined by immunofluorescence staining, co-immuno-precipitation, and immunohistochemistry. HE and immunofluorescence staining were used to confirm the establishment of CRC organoid models. Patient-derived xenograft (PDX) and nude mouse subcutaneous xenografts were used to evaluate the in vivo effect of targeting DSPP on oxaliplatin response.

[RESULTS] DSPP expression was significantly elevated in oxaliplatin-resistant patients and in oxaliplatin-resistant HCT8 cells. DSPP knockout significantly increased oxaliplatin sensitivity in oxaliplatin-resistant HCT8 cells and in HCT116 and SW620 cells. Co-immunoprecipitation revealed binding between DSPP and integrin αvβ3 in tumor cells, and immunofluorescence staining demonstrated their co-localization. Immunohistochemistry showed a positive correlation between DSPP expression and integrin αvβ3 expression in CRC tissues. Western blotting indicated that DSPP upregulated the phosphorylation levels of ERK and P53 in the MAPK signaling pathway, whereas the integrin αvβ3-targeted inhibitor (Cyclo) effectively abrogated this regulatory effect. In the xenograft and PDX models, targeted inhibition of DSPP or integrin αvβ3 suppressed tumor growth and improved the efficacy of oxaliplatin, for which the anti-DSPP monoclonal antibody was more effective than integrin αvβ3-targeted inhibitor.

[CONCLUSIONS] We identified a DSPP-integrin αvβ3 axis that mediates oxaliplatin resistance, and DSPP may serve as a therapeutic target to restore chemosensitivity in advanced CRC.