Background and Aims:Metastasis is a major factor associated with high recurrence and mortality in hepatocellular carcinoma(HCC)patients while the underlying mechanism of metastasis remains elusive.In our study,procoll...Background and Aims:Metastasis is a major factor associated with high recurrence and mortality in hepatocellular carcinoma(HCC)patients while the underlying mechanism of metastasis remains elusive.In our study,procollagen-lysine,2-oxoglutarate 5-dioxygenase 2(PLOD2)was shown to be involved in the process of metastasis in HCC.Methods:The Cancer Genome Atlas(TCGA)database and HCC tissue microarrays were used to evaluate the expression of genes.In vitro migration,invasion,in vivo subcutaneous tumor model and in vivo lung metastasis assays were used to determine the role of PLOD2 in tumor growth and metastasis in HCC.RNA sequencing and gene set enrichment analysis were performed to uncover the downstream factor of PLOD2 in HCC cells.A luciferase reporter assay was performed to evaluate the interaction between PLOD2 and interferon regulatory factor 5(IRF5).Results:The expression of PLOD2 in HCC tissues was higher than that in adjacent tissues,and increased PLOD2 expression was often found in advanced tumors and was correlated with poor prognosis in HCC patients.In vitro experiments,knockdown of PLOD2 reduced the migration and invasion of human HCC cells.Loss of PLOD2 suppressed human HCC growth and metastasis in a subcutaneous tumor model and a lung metastasis model.Baculoviral IAP repeat containing 3(BIRC3)was proven to be the downstream factor of PLOD2 in human HCC cells.In addition,PLOD2 was transcriptionally regulated by IRF5 in HCC cells.Conclusions:High expression of PLOD2 was regulated by IRF5,which was correlated with the poor survival of HCC patients.PLOD2 enhanced HCC metastasis via BIRC3,suggesting that PLOD2 might be a valuable prognostic biomarker for HCC treatment.展开更多
Background:Tumor-derived exosomes are involved in tumor progression and immune invasion and might func-tion as promising noninvasive approaches for clinical management.However,there are few reports on exosom-based mar...Background:Tumor-derived exosomes are involved in tumor progression and immune invasion and might func-tion as promising noninvasive approaches for clinical management.However,there are few reports on exosom-based markers for predicting the progression and adjuvant therapy response rate among patients with clear cell renal cell carcinoma(ccRCC).Methods:The signatures differentially expressed in exosomes from tumor and normal tissues from ccRCC pa-tients were correspondingly deregulated in ccRCC tissues.We adopted a two-step strategy,including Lasso and bootstrapping,to construct a novel risk stratification system termed the TDERS(Tumor-Derived Exosome-Related Risk Score).During the testing and validation phases,we leveraged multiple external datasets containing over 2000 RCC cases from eight cohorts and one inhouse cohort to evaluate the accuracy of the TDERS.In addition,enrichment analysis,immune infiltration signatures,mutation landscape and therapy sensitivity between the high and low TDERS groups were compared.Finally,the impact of TDERS on the tumor microenvironment(TME)was also analysed in our single-cell datasets.Results:TDERS consisted of 12 mRNAs deregulated in both exosomes and tissues from patients with ccRCC.TDERS achieved satisfactory performance in both prognosis and immune checkpoint inhibitor(ICI)response across all ccRCC cohorts and other pathological types,since the average area under the curve(AUC)to predict 5-year overall survival(OS)was larger than 0.8 across the four cohorts.Patients in the TDERS high group were resistant to ICIs,while mercaptopurine might function as a promising agent for those patients.Patients with a high TDERS were characterized by coagulation and hypoxia,which induced hampered tumor antigen presentation and relative resistance to ICIs.In addition,single cells from 12 advanced samples validated this phenomenon since the interaction between dendritic cells and macrophages was limited.Finally,PLOD2,which is highly expressed in fibro-and epi-tissue,could be a potential therapeutic target for ccRCC patients since inhibiting PLOD2 altered the malignant phenotype of ccRCC in vitro.Conclusion:As a novel,non-invasive,and repeatable monitoring tool,the TDERS could work as a robust risk stratification system for patients with ccRCC and precisely inform treatment decisions about ICI therapy.展开更多
基金supported by grants from the National Natural Science Foundation of China(Nos.81902473,82172815,and 82103601).
文摘Background and Aims:Metastasis is a major factor associated with high recurrence and mortality in hepatocellular carcinoma(HCC)patients while the underlying mechanism of metastasis remains elusive.In our study,procollagen-lysine,2-oxoglutarate 5-dioxygenase 2(PLOD2)was shown to be involved in the process of metastasis in HCC.Methods:The Cancer Genome Atlas(TCGA)database and HCC tissue microarrays were used to evaluate the expression of genes.In vitro migration,invasion,in vivo subcutaneous tumor model and in vivo lung metastasis assays were used to determine the role of PLOD2 in tumor growth and metastasis in HCC.RNA sequencing and gene set enrichment analysis were performed to uncover the downstream factor of PLOD2 in HCC cells.A luciferase reporter assay was performed to evaluate the interaction between PLOD2 and interferon regulatory factor 5(IRF5).Results:The expression of PLOD2 in HCC tissues was higher than that in adjacent tissues,and increased PLOD2 expression was often found in advanced tumors and was correlated with poor prognosis in HCC patients.In vitro experiments,knockdown of PLOD2 reduced the migration and invasion of human HCC cells.Loss of PLOD2 suppressed human HCC growth and metastasis in a subcutaneous tumor model and a lung metastasis model.Baculoviral IAP repeat containing 3(BIRC3)was proven to be the downstream factor of PLOD2 in human HCC cells.In addition,PLOD2 was transcriptionally regulated by IRF5 in HCC cells.Conclusions:High expression of PLOD2 was regulated by IRF5,which was correlated with the poor survival of HCC patients.PLOD2 enhanced HCC metastasis via BIRC3,suggesting that PLOD2 might be a valuable prognostic biomarker for HCC treatment.
基金funded by grants from the National Natural Science Foundation of China(grant numbers:82002664,81872074,81772740,82173345 and 82373154)the Hanghai Jiading District Health Commission Scientific Research Project Youth Fund(grant num-ber:2020-QN-02)the Meng Chao Talent Training Plan-Youth Re-search Talent Training Program of Eastern Hepatobiliary Surgery Hos-pital and the Foundation for Distinguished Youths of Jiangsu Province(grant number:BK20200006).
文摘Background:Tumor-derived exosomes are involved in tumor progression and immune invasion and might func-tion as promising noninvasive approaches for clinical management.However,there are few reports on exosom-based markers for predicting the progression and adjuvant therapy response rate among patients with clear cell renal cell carcinoma(ccRCC).Methods:The signatures differentially expressed in exosomes from tumor and normal tissues from ccRCC pa-tients were correspondingly deregulated in ccRCC tissues.We adopted a two-step strategy,including Lasso and bootstrapping,to construct a novel risk stratification system termed the TDERS(Tumor-Derived Exosome-Related Risk Score).During the testing and validation phases,we leveraged multiple external datasets containing over 2000 RCC cases from eight cohorts and one inhouse cohort to evaluate the accuracy of the TDERS.In addition,enrichment analysis,immune infiltration signatures,mutation landscape and therapy sensitivity between the high and low TDERS groups were compared.Finally,the impact of TDERS on the tumor microenvironment(TME)was also analysed in our single-cell datasets.Results:TDERS consisted of 12 mRNAs deregulated in both exosomes and tissues from patients with ccRCC.TDERS achieved satisfactory performance in both prognosis and immune checkpoint inhibitor(ICI)response across all ccRCC cohorts and other pathological types,since the average area under the curve(AUC)to predict 5-year overall survival(OS)was larger than 0.8 across the four cohorts.Patients in the TDERS high group were resistant to ICIs,while mercaptopurine might function as a promising agent for those patients.Patients with a high TDERS were characterized by coagulation and hypoxia,which induced hampered tumor antigen presentation and relative resistance to ICIs.In addition,single cells from 12 advanced samples validated this phenomenon since the interaction between dendritic cells and macrophages was limited.Finally,PLOD2,which is highly expressed in fibro-and epi-tissue,could be a potential therapeutic target for ccRCC patients since inhibiting PLOD2 altered the malignant phenotype of ccRCC in vitro.Conclusion:As a novel,non-invasive,and repeatable monitoring tool,the TDERS could work as a robust risk stratification system for patients with ccRCC and precisely inform treatment decisions about ICI therapy.
