Background:Cisplatin-based chemotherapy with concurrent radiotherapy is a standard treatment for advanced esophageal squamous cell carcinoma(ESCC).NS1-binding protein(NS1-BP),a member of the BTB-kelch protein fam-ily,...Background:Cisplatin-based chemotherapy with concurrent radiotherapy is a standard treatment for advanced esophageal squamous cell carcinoma(ESCC).NS1-binding protein(NS1-BP),a member of the BTB-kelch protein fam-ily,has been shown to inhibit the proliferation of Hela cells by suppressing c-Myc.In the present study,we examined the potential function role of NS1-BP expression in ESCC,and particularly,the sensitivity of ESCC to radiotherapy.Methods:NS1-BP expression was examined using immunohistochemistry in two cohorts(n=98 for the training cohort;n=46 for independent validation cohort)of ESCC patients receiving cisplatin-based chemotherapy and con-current radiotherapy.Normal esophageal mucosal tissue blocks were used as a control.We also conducted a series of in vitro and in vivo experiments to examine the potential effects of over-expressing NS1-BP on ESCC cells,and particu-larly their sensitivity to ionizing irradiation.Results:In the training cohort,NS1-BP downregulation was observed in 59%(85/144)of the ESCC specimens.NS1-BP downregulation was associated with chemoradiotherapeutic resistance and shorter disease-specific survival(DSS)in both the training and validation cohorts.Over-expressing NS1-BP in cultured ESCC cells substantially increased the cellular response to irradiation both in vitro and in vivo.NS1-BP also significantly enhanced IR-induced apoptosis,and abrogated IR-induced G2/M cell-cycle arrest and ATM/Chk1 phosphorylation.Immunoprecipitation assays indicated that NS1-BP could interact with c-Myc promoter regions to inhibit its transcription.In ESCC tissues,c-Myc expression was inversely correlated with NS1-BP levels,and was associated with a shorter DSS.Conclusions:Our findings highlight the role and importance of NS1-BP in radiosensitivity of ESCC.Targeting the NS1-BP/c-Myc pathway may provide a novel therapeutic strategy for ESCC.展开更多
基金supported by the National Nature Science Foundation of China(81401948,81472182,81372518 and 81472797).
文摘Background:Cisplatin-based chemotherapy with concurrent radiotherapy is a standard treatment for advanced esophageal squamous cell carcinoma(ESCC).NS1-binding protein(NS1-BP),a member of the BTB-kelch protein fam-ily,has been shown to inhibit the proliferation of Hela cells by suppressing c-Myc.In the present study,we examined the potential function role of NS1-BP expression in ESCC,and particularly,the sensitivity of ESCC to radiotherapy.Methods:NS1-BP expression was examined using immunohistochemistry in two cohorts(n=98 for the training cohort;n=46 for independent validation cohort)of ESCC patients receiving cisplatin-based chemotherapy and con-current radiotherapy.Normal esophageal mucosal tissue blocks were used as a control.We also conducted a series of in vitro and in vivo experiments to examine the potential effects of over-expressing NS1-BP on ESCC cells,and particu-larly their sensitivity to ionizing irradiation.Results:In the training cohort,NS1-BP downregulation was observed in 59%(85/144)of the ESCC specimens.NS1-BP downregulation was associated with chemoradiotherapeutic resistance and shorter disease-specific survival(DSS)in both the training and validation cohorts.Over-expressing NS1-BP in cultured ESCC cells substantially increased the cellular response to irradiation both in vitro and in vivo.NS1-BP also significantly enhanced IR-induced apoptosis,and abrogated IR-induced G2/M cell-cycle arrest and ATM/Chk1 phosphorylation.Immunoprecipitation assays indicated that NS1-BP could interact with c-Myc promoter regions to inhibit its transcription.In ESCC tissues,c-Myc expression was inversely correlated with NS1-BP levels,and was associated with a shorter DSS.Conclusions:Our findings highlight the role and importance of NS1-BP in radiosensitivity of ESCC.Targeting the NS1-BP/c-Myc pathway may provide a novel therapeutic strategy for ESCC.
