Objective:Androgen receptor(AR)signaling is a central driver of prostate cancer progression,yet the metabolic and transcriptional mechanisms regulating AR expression remain incompletely characterized.This study invest...Objective:Androgen receptor(AR)signaling is a central driver of prostate cancer progression,yet the metabolic and transcriptional mechanisms regulating AR expression remain incompletely characterized.This study investigated whether the immunoproteasome inhibitor ONX-0914 suppresses hormone-sensitive prostate cancer(HSPC)through metabolic modulation of AR and aimed to identify the transcriptional mediator involved.Methods:HSPC and castration-resistant prostate cancer models were used to evaluate the effects of ONX-0914 on cell proliferation,invasion,migration,and epithelial-mesenchymal transition.Xenograft assays,bioinformatic screening,and analyses of O-GlcNAcylation and protein stability were performed,together with quantitative polymerase chain reaction(qPCR)and Western blotting.Results:ONX-0914 markedly suppressed hormone-sensitive prostate cancer(HSPC)progression through both LMP7-dependent and LMP7-independent mechanisms.Mechanistically,ONX-0914 activated the hexosamine biosynthetic pathway and enhanced global O-GlcNAcylation,leading to stabilization of the transcriptional repressor Transcription factor 7-like 1(TCF7L1)and consequent suppression of androgen receptor(AR)expression.Functionally,activation of the O-GlcNAcylation-TCF7L1 axis inhibited cell proliferation,invasion,migration,and epithelial-mesenchymal transition in vitro.In vivo,TCF7L1 overexpression,particularly under conditions of enhanced O-GlcNAcylation,significantly suppressed tumor growth and AR expression.Conclusion:This study identifies a novel ONX-0914/HBP/TCF7L1 O-GlcNAcylation axis that metabolically stabilizes TCF7L1,leading to repression of AR signaling and inhibition of HSPC progression.These findings reveal a previously unrecognized metabolic-transcriptional regulatory mechanism and highlight TCF7L1 O-GlcNAcylation as a potential therapeutic target in AR-dependent prostate cancer.展开更多
Non-small cell lung cancer(NSCLC)is a leading cause of cancer-related mortality worldwide1-3.While radioimmuno-therapy shows promise in boosting antitumor immunity,the clinical outcomes have been inconsistent4 and are...Non-small cell lung cancer(NSCLC)is a leading cause of cancer-related mortality worldwide1-3.While radioimmuno-therapy shows promise in boosting antitumor immunity,the clinical outcomes have been inconsistent4 and are often lim-ited by the immunosuppressive tumor microenvironment(TME).Cyclooxygenase(COX)-2 and the COX-2 downstream product,prostaglandin E2(PGE2),are increasingly implicated in immune escape5,6 but the impact on radioimmunother-apy efficacy has not been explored.TCF1-expressing CD8+T cells demonstrate defining functional properties of progeni-tor-exhausted T cells,including clonal expansion through self-renewal capacity and multipotent differentiation toward terminal effector phenotypes,while maintaining long-term persistence critical for sustaining antitumor immunity7-9.Given the central role in anti-tumor immune maintenance,TCF1+CD8+T cells are likely critical to radioimmunotherapy efficacy10.The role of COX-2 inhibition in enhancing the effi-cacy of radioimmunotherapy efficacy in NSCLC was investi-gated in the current study.展开更多
针对末端夹持激光位移传感器的机器人TCF(tool/terminal control frame)标定,提出一种基于平面模扳的标定方法,机器人操作末端执行器使激光位移传感器在不同位形下对平面模板进行测量,再通过非线性最小.乘拟合求解标定参数.为了减小问...针对末端夹持激光位移传感器的机器人TCF(tool/terminal control frame)标定,提出一种基于平面模扳的标定方法,机器人操作末端执行器使激光位移传感器在不同位形下对平面模板进行测量,再通过非线性最小.乘拟合求解标定参数.为了减小问题的奇异性,对标定时应该采取的参数控制策略进行了定性分析.该标定方法只需要一块表面精度较高的平面模板,而无需其它测量仪器,标定过程简单、易操作,且易于实现自动己.仿真和实验结果表明本文提出的标定方法具有较高的精度.展开更多
文摘Objective:Androgen receptor(AR)signaling is a central driver of prostate cancer progression,yet the metabolic and transcriptional mechanisms regulating AR expression remain incompletely characterized.This study investigated whether the immunoproteasome inhibitor ONX-0914 suppresses hormone-sensitive prostate cancer(HSPC)through metabolic modulation of AR and aimed to identify the transcriptional mediator involved.Methods:HSPC and castration-resistant prostate cancer models were used to evaluate the effects of ONX-0914 on cell proliferation,invasion,migration,and epithelial-mesenchymal transition.Xenograft assays,bioinformatic screening,and analyses of O-GlcNAcylation and protein stability were performed,together with quantitative polymerase chain reaction(qPCR)and Western blotting.Results:ONX-0914 markedly suppressed hormone-sensitive prostate cancer(HSPC)progression through both LMP7-dependent and LMP7-independent mechanisms.Mechanistically,ONX-0914 activated the hexosamine biosynthetic pathway and enhanced global O-GlcNAcylation,leading to stabilization of the transcriptional repressor Transcription factor 7-like 1(TCF7L1)and consequent suppression of androgen receptor(AR)expression.Functionally,activation of the O-GlcNAcylation-TCF7L1 axis inhibited cell proliferation,invasion,migration,and epithelial-mesenchymal transition in vitro.In vivo,TCF7L1 overexpression,particularly under conditions of enhanced O-GlcNAcylation,significantly suppressed tumor growth and AR expression.Conclusion:This study identifies a novel ONX-0914/HBP/TCF7L1 O-GlcNAcylation axis that metabolically stabilizes TCF7L1,leading to repression of AR signaling and inhibition of HSPC progression.These findings reveal a previously unrecognized metabolic-transcriptional regulatory mechanism and highlight TCF7L1 O-GlcNAcylation as a potential therapeutic target in AR-dependent prostate cancer.
基金funded by the National Natural Science Foundation of China(Grant Nos.82030082 and 82272845)the Natural Science Foundation of Shandong Province(Grant No.ZR2023LZL001).
文摘Non-small cell lung cancer(NSCLC)is a leading cause of cancer-related mortality worldwide1-3.While radioimmuno-therapy shows promise in boosting antitumor immunity,the clinical outcomes have been inconsistent4 and are often lim-ited by the immunosuppressive tumor microenvironment(TME).Cyclooxygenase(COX)-2 and the COX-2 downstream product,prostaglandin E2(PGE2),are increasingly implicated in immune escape5,6 but the impact on radioimmunother-apy efficacy has not been explored.TCF1-expressing CD8+T cells demonstrate defining functional properties of progeni-tor-exhausted T cells,including clonal expansion through self-renewal capacity and multipotent differentiation toward terminal effector phenotypes,while maintaining long-term persistence critical for sustaining antitumor immunity7-9.Given the central role in anti-tumor immune maintenance,TCF1+CD8+T cells are likely critical to radioimmunotherapy efficacy10.The role of COX-2 inhibition in enhancing the effi-cacy of radioimmunotherapy efficacy in NSCLC was investi-gated in the current study.
文摘针对末端夹持激光位移传感器的机器人TCF(tool/terminal control frame)标定,提出一种基于平面模扳的标定方法,机器人操作末端执行器使激光位移传感器在不同位形下对平面模板进行测量,再通过非线性最小.乘拟合求解标定参数.为了减小问题的奇异性,对标定时应该采取的参数控制策略进行了定性分析.该标定方法只需要一块表面精度较高的平面模板,而无需其它测量仪器,标定过程简单、易操作,且易于实现自动己.仿真和实验结果表明本文提出的标定方法具有较高的精度.
