Lysosomal dysfunction has been implicated in the progression of colon adenocarcinoma(COAD),yet the prognostic significance and therapeutic potential of lysosome-related genes(LRGs)remain underexplored.In this study,we...Lysosomal dysfunction has been implicated in the progression of colon adenocarcinoma(COAD),yet the prognostic significance and therapeutic potential of lysosome-related genes(LRGs)remain underexplored.In this study,we construct a 6-LRG-based prognostic risk stratification model(DPP7,ADAM8,CD1B,LRP2,ATP6V1C2,and PLAAT3)by integrating LASSO and Cox regression analyses.Stratifying patients based on median risk scores,we demonstrate that high-risk patients exhibit significantly worse clinical outcomes across the TCGA cohort and five independent GEO datasets.Furthermore,this panel outperforms 136 previously published models in terms of predictive accuracy for 1-,3-,and 5-year survival rates.Validation multiplex immunofluorescence using an in-house tissue microarray cohort confirms that the 6-LRG signature serves as an independent prognostic factor.Additionally,high-risk patients exhibit distinct immunosuppressive tumor microenvironment and aggressive malignancy characteristics.Functional depletion of DPP7 significantly inhibits tumor cell proliferation,migration,and metastasis in both in vitro and in vivo settings.Moreover,DPP7 silencing attenuates epithelialemesenchymal transition,as evidenced by the upregulation of E-cadherin and downregulation of N-cadherin,Vimentin,and Snail.In conclusion,this study establishes an LRG-based model for COAD prognostic prediction and nominates DPP7 as a promising therapeutic target for COAD treatment.展开更多
基金supported by the Natural Science Foundation of Shandong Province(ZR2021MH110,ZR2020MH257,ZR2020MH323)the National Natural Science Foundation of China(82172339 and 82272410)+1 种基金Major Scientific and Technological Innovation Project of Shandong Province(2021CXGC010603 and 2021CXGC011105)Taishan Scholar Program of Shandong Province(tstp20221156 and tsqn202306346).
文摘Lysosomal dysfunction has been implicated in the progression of colon adenocarcinoma(COAD),yet the prognostic significance and therapeutic potential of lysosome-related genes(LRGs)remain underexplored.In this study,we construct a 6-LRG-based prognostic risk stratification model(DPP7,ADAM8,CD1B,LRP2,ATP6V1C2,and PLAAT3)by integrating LASSO and Cox regression analyses.Stratifying patients based on median risk scores,we demonstrate that high-risk patients exhibit significantly worse clinical outcomes across the TCGA cohort and five independent GEO datasets.Furthermore,this panel outperforms 136 previously published models in terms of predictive accuracy for 1-,3-,and 5-year survival rates.Validation multiplex immunofluorescence using an in-house tissue microarray cohort confirms that the 6-LRG signature serves as an independent prognostic factor.Additionally,high-risk patients exhibit distinct immunosuppressive tumor microenvironment and aggressive malignancy characteristics.Functional depletion of DPP7 significantly inhibits tumor cell proliferation,migration,and metastasis in both in vitro and in vivo settings.Moreover,DPP7 silencing attenuates epithelialemesenchymal transition,as evidenced by the upregulation of E-cadherin and downregulation of N-cadherin,Vimentin,and Snail.In conclusion,this study establishes an LRG-based model for COAD prognostic prediction and nominates DPP7 as a promising therapeutic target for COAD treatment.
