靶向 WDxR 基序重编程免疫微环境并抑制肝细胞癌进展,EMBO Molecular Medicine

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靶向 WDxR 基序重编程免疫微环境并抑制肝细胞癌进展
EMBO Molecular Medicine ( IF 9.0 ) Pub Date : 2023-03-22 , DOI: 10.15252/emmm.202215924
Heng Zhang _{1,

2} , Gang Chen ₃ , Xing Feng ₄ , Huiwen Song ₅ , Lingbing Meng ₆ , Yao Fu ₇ , Jun Yang ₇ , Zhiwen Fan ₇ , Youxiang Ding ₇ , Zhijie Du ₈ , Jianchao Wang ₃ , Li Yang _{9,

10} , Jun Zhang ₁₁ , Lixia Sun ₁₂ , Zhigang Liu ₁₂ , Zhiyong Zhang _{13,

14} , Quanhai Li ₁₅ , Xiangshan Fan ₇

Affiliation

Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
Department of Histology and Embryology, Xiang Ya School of Medicine, Central South University, Changsha, China.
Department of Pathology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China.
Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
Department of Cardiology, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China.
Departments of Cardiology, Beijing Hospital, National Center of Gerontology, Chinese Academy of Medical Sciences, Beijing, China.
Department of Pathology, The Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
Institute of Digestive Disease, China Three Gorges University, Yichang, China.
Department of Gastroenterology, Yichang Central People's Hospital, Yichang, China.
Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, China.
Department of Hepatological Surgery, The Affiliated Wuhu hospital of ECNU, Wuhu, China.
Department of Surgery, Robert-Wood-Johnson Medical School University Hospital, Rutgers University, New Brunswick, NJ, USA.
National Center for International Research of Biological Targeting Diagnosis and Therapy, Guangxi Medical University, Nanning, China.
Cell Therapy Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, China.

WD 重复 (WDR) 家族影响致癌作用，但其在免疫微环境中的作用尚不清楚。尽管 WDR6 的功能丧失或获得不会显着改变HCC 细胞的体外增殖和侵袭能力，但其在 hepa1-6 细胞中的缺陷会显着抑制具有免疫能力的 C57BL/6J 小鼠原位植入肿瘤的生长和肺转移。从机制上讲，WDR6 通过独特的 WDxR 基序将肿瘤抑制因子 UVRAG 靶向 CUL4A-DDB1-ROC1 E3 泛素连接酶复合物并促进其降解。这通过阻断 p65 的自噬降解来上调 TNFα 基因座的染色质可及性，增加肿瘤内髓源性抑制细胞 (MDSC) 的数量，并减少 CD8 ⁺T 细胞浸润，从而促进 HCC 进展。这些免疫抑制作用可被 TNFα 阻断剂逆转。TNFα 募集 NF-κB 以激活WDR6的转录，建立 WDR6-TNFα 环。临床上，WDR6/UVRAG/NF-κB 通路在 HCC 中过度激活，预示着预后不良。重要的是，WDxR 样肽会破坏 WDR6/UVRAG 复合物，并提高抗 PD-L1 抗 HCC 与 WDR6 失调的效率。

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更新日期：2023-03-22

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