Background:Exploring the underlying mechanism of rituximab resistance is critical to improve the outcomes of patients with diffuse large B-cell lymphoma(DLBCL).Here,we tried to identify the effects of the axon guidanc...Background:Exploring the underlying mechanism of rituximab resistance is critical to improve the outcomes of patients with diffuse large B-cell lymphoma(DLBCL).Here,we tried to identify the effects of the axon guidance factor semaphorin-3F(SEMA3F)on rituximab resistance as well as its therapeutic value in DLBCL.Methods:The effects of SEMA3F on the treatment response to rituximab were investigated by gain-or loss-of-function experiments.The role of the Hippo pathway in SEMA3F-mediated activity was explored.A xenograft mouse model generated by SEMA3F knockdown in cells was used to evaluate rituximab sensitivity and combined therapeutic effects.The prognostic value of SEMA3F and TAZ(WW domain-containing transcription regulator protein 1)was examined in the Gene Expression Omnibus(GEO)database and human DLBCL specimens.Results:We found that loss of SEMA3F was related to a poor prognosis in patients who received rituximab-based immunochemotherapy instead of chemotherapy regimen.Knockdown of SEMA3F significantly repressed the expression of CD20 and reduced the proapoptotic activity and complement-dependent cytotoxicity(CDC)activity induced by rituximab.We further demonstrated that the Hippo pathway was involved in the SEMA3F-mediated regulation of CD20.Knockdown of SEMA3F expression induced the nuclear accumulation of TAZ and inhibited CD20 transcriptional levels via direct binding of the transcription factor TEAD2 and the CD20 promoter.Moreover,in patients with DLBCL,SEMA3F expression was negatively correlated with TAZ,and patients with SEMA3F^(low)TAZ^(high)had a limited benefit from a rituximab-based strategy.Specifically,treatment of DLBCL cells with rituximab and a YAP/TAZ inhibitor showed promising therapeutic effects in vitro and in vivo.Conclusion:Our study thus defined a previously unknown mechanism of SEMA3F-mediated rituximab resistance through TAZ activation in DLBCL and identified potential therapeutic targets in patients.展开更多
基金National Natural Science Fund(No.82070208)National Natural Science Foundation of Chongqing(cstc2020jcyjmsxmX0433)+4 种基金Major program of Chongqing Health Commission and Science and Technology Bureau Joint project(2022DBXM003)Chongqing Science and Health Joint medical research project(2023QNXM047)Military clinical medical innovation project of Xinqiao hospital(2021JSLC0003)Science and technology innovation promotion project of AMU(2019XLC3020)Translational Research Grant of NCRCH(2020ZKZC02 and 2021WWB05)
文摘Background:Exploring the underlying mechanism of rituximab resistance is critical to improve the outcomes of patients with diffuse large B-cell lymphoma(DLBCL).Here,we tried to identify the effects of the axon guidance factor semaphorin-3F(SEMA3F)on rituximab resistance as well as its therapeutic value in DLBCL.Methods:The effects of SEMA3F on the treatment response to rituximab were investigated by gain-or loss-of-function experiments.The role of the Hippo pathway in SEMA3F-mediated activity was explored.A xenograft mouse model generated by SEMA3F knockdown in cells was used to evaluate rituximab sensitivity and combined therapeutic effects.The prognostic value of SEMA3F and TAZ(WW domain-containing transcription regulator protein 1)was examined in the Gene Expression Omnibus(GEO)database and human DLBCL specimens.Results:We found that loss of SEMA3F was related to a poor prognosis in patients who received rituximab-based immunochemotherapy instead of chemotherapy regimen.Knockdown of SEMA3F significantly repressed the expression of CD20 and reduced the proapoptotic activity and complement-dependent cytotoxicity(CDC)activity induced by rituximab.We further demonstrated that the Hippo pathway was involved in the SEMA3F-mediated regulation of CD20.Knockdown of SEMA3F expression induced the nuclear accumulation of TAZ and inhibited CD20 transcriptional levels via direct binding of the transcription factor TEAD2 and the CD20 promoter.Moreover,in patients with DLBCL,SEMA3F expression was negatively correlated with TAZ,and patients with SEMA3F^(low)TAZ^(high)had a limited benefit from a rituximab-based strategy.Specifically,treatment of DLBCL cells with rituximab and a YAP/TAZ inhibitor showed promising therapeutic effects in vitro and in vivo.Conclusion:Our study thus defined a previously unknown mechanism of SEMA3F-mediated rituximab resistance through TAZ activation in DLBCL and identified potential therapeutic targets in patients.
