南方医科大学学报2026，Vol.46Issue(3)：479-488,10.DOI:10.12122/j.issn.1673-4254.2026.03.01
结直肠癌细胞分泌牙本质涎磷蛋白通过整合素αvβ3依赖途径诱导奥沙利铂耐药
Tumor-secreted dentin sialophosphoprotein induces oxaliplatin resistance in colorectal cancer through an integrin αvβ3-dependent pathway
摘要
Abstract
Objective 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.Conclusion 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.关键词
结直肠癌/化疗耐药/牙本质涎磷蛋白/整合素αvβ3Key words
colorectal cancer/chemotherapy resistance/dentin sialophosphoprotein/integrin αvβ3引用本文复制引用
刘超群,宁紫燕,吴江华,刘魏魏,林创,许嘉玮,周蕊,赵亮..结直肠癌细胞分泌牙本质涎磷蛋白通过整合素αvβ3依赖途径诱导奥沙利铂耐药[J].南方医科大学学报,2026,46(3):479-488,10.基金项目
国家自然科学基金(82403601) （82403601）
广州市科技计划项目(2024A04J5178) （2024A04J5178）
广东省基础与应用基础研究基金(2024A1515012738)Supported by National Natural Science Foundation of China(82403601). （2024A1515012738）
