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摘要:The tumor microenvironment plays an important role in tumor growth and metastasis.However,the mechanism by which tumor cells regulate the cell and non-cell constituents of surrounding stroma remains incompletely understood.PML is a pleiotropic tumor suppressor but its role in tumor microenvironment regulation is poorly characterized.PML protein is frequently downregulated in many cancer types,including lung cancer.Here,we identify a novel PML ubiquitination/destruction pathway mediated by ubiquitin ligase CRL4WDR4.Clinically,this PML destruction pathway is hyperactivated in lung cancer and correlates with poor prognosis.The WDR4/PML axis induces a set of cell surface or secreted factors,including CD73,uPAR,and SAA2,which elicit paracrine effects to stimulate migration,invasion,and metastasis in multiple lung cancer models.Furthermore,in both xenograft and genetically engineered mouse models,the WDR4/PML axis elevates intratumoral Tregs and M2-like macrophages and reduces CD8+ T cells to promote lung tumor growth and these immunosuppressive effects are all reversed by CD73 blockade.Our study identifies WDR4 as a novel oncoprotein which negatively regulates PML via ubiquitination to promote lung cancer progression by fostering an immunosuppressive and pro-metastatic tumor microenvironment and suggests a potential of immune-modulatory approaches for treating lung cancer with aberrant PML degradation.
会议名称:

全球华人生物学家大会暨第十六届美洲华人生物科学学会学术研讨会

会议时间:

2017-06-29

会议地点:

中国浙江杭州

  • 专辑:

    医药卫生

  • 专题:

    肿瘤学

  • 分类号:

    R734.2

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