例如:"lncRNA", "apoptosis", "WRKY"

Ubiquitination of tumor suppressor PML regulates prometastatic and immunosuppressive tumor microenvironment.

J. Clin. Invest.2017 Aug 01;127(8):2982-2997. Epub 2017 Jul 10
Ya-Ting Wang 1 , Jocelyn Chen 1 , Chou-Wei Chang 2 , Jayu Jen 3 , Tzu-Yu Huang 2 , Chun-Ming Chen 2 , Roger Shen 4 , Suh-Yuen Liang 2 , I-Cheng Cheng 5 , Shuenn-Chen Yang 4 , Wu-Wei Lai 6 , Kuang-Hung Cheng 7 , Tao-Shih Hsieh 5 , Ming-Zong Lai 8 , Hung-Chi Cheng 9 , Yi-Ching Wang 3 , Ruey-Hwa Chen 1
Ya-Ting Wang 1 , Jocelyn Chen 1 , Chou-Wei Chang 2 , Jayu Jen 3 , Tzu-Yu Huang 2 , Chun-Ming Chen 2 , Roger Shen 4 , Suh-Yuen Liang 2 , I-Cheng Cheng 5 , Shuenn-Chen Yang 4 , Wu-Wei Lai 6 , Kuang-Hung Cheng 7 , Tao-Shih Hsieh 5 , Ming-Zong Lai 8 , Hung-Chi Cheng 9 , Yi-Ching Wang 3 , Ruey-Hwa Chen 1
+ et al

[No authors listed]

Author information
  • 1 Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan.
  • 2 Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
  • 3 Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • 4 Institute of Biomedical Sciences and.
  • 5 Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
  • 6 Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan.
  • 7 Graduate Institute of Biomedical Science, National Sun Yat-Sen University, Kaoshiung, Taiwan.
  • 8 Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
  • 9 Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

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. Promyelocytic leukemia (PML) is a pleiotropic tumor suppressor, but its role in tumor microenvironment regulation is poorly characterized. PML is frequently downregulated in many cancer types, including lung cancer. Here, we identify a PML ubiquitination pathway that is mediated by WD repeat 4-containing cullin-RING ubiquitin ligase 4 (CRL4WDR4). Clinically, this PML degradation 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, urokinase-type plasminogen activator receptor (uPAR), and serum amyloid A2 (SAA2), which elicit paracrine effects to stimulate migration, invasion, and metastasis in multiple lung cancer models. In 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. These immunosuppressive effects were all reversed by CD73 blockade. Our study identifies WDR4 as an oncoprotein that negatively regulates PML via ubiquitination to promote lung cancer progression by fostering an immunosuppressive and prometastatic tumor microenvironment, suggesting the potential of immune-modulatory approaches for treating lung cancer with aberrant PML degradation.