The innate immune effector ISG12a promotes cancer immunity by suppressing the canonical Wnt/β-catenin signaling pathway

被引：59

作者：

Deng, Rilin ^{[1
]}

Zuo, Chaohui ^{[2
]}

Li, Yongqi ^{[3
]}

Xue, Binbin ^{[1
]}

Xun, Zhen ^{[1
]}

Guo, Yanxia ^{[1
]}

Wang, Xiaohong ^{[1
]}

Xu, Yan ^{[1
]}

Tian, Renyun ^{[1
]}

Chen, Shengwen ^{[1
]}

Liu, Qian ^{[1
]}

Chen, Jinwen ^{[1
]}

Wang, Jingjing ^{[1
]}

Huang, Xiang ^{[1
]}

Li, Huiyi ^{[1
]}

Guo, Mengmeng ^{[1
]}

Wang, Xintao ^{[1
]}

Yang, Miaomiao ^{[3
]}

Wu, Zhihui ^{[3
]}

Wang, Jinfeng ^{[2
]}

Ma, Jiahuan ^{[1
]}

Hu, Jun ^{[4
]}

Li, Guangdi ^{[5
]}

Tang, Songqing ^{[1
]}

Tu, Zhengkun ^{[3
]}

Ji, Hongbin ^{[6
,7
]}

Zhu, Haizhen ^{[1
,2
]}

机构：

[1] Hunan Univ, Inst Pathogen Biol & Immunol, Hunan Prov Key Lab Med Virol, State Key Lab Chemo Biosensing & Chemometr,Coll B, Changsha 410082, Hunan, Peoples R China

[2] Hunan Canc Hosp, Res Ctr Canc Prevent & Treatment, Translat Med Res Ctr Liver Canc, Changsha 410013, Hunan, Peoples R China

[3] Jilin Univ, Inst Translat Med, Inst Liver Dis, Hosp 1, Changchun 130061, Jilin, Peoples R China

[4] Hunan Canc Hosp, Dept Pathol, Changsha 410013, Hunan, Peoples R China

[5] Cent South Univ, Dept Publ Hlth, Changsha 410078, Hunan, Peoples R China

[6] Univ Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, Chinese Acad Sci, State Key Lab Cell Biol,CAS Ctr Excellence Mol Ce, Shanghai 200031, Peoples R China

[7] Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 200120, Peoples R China

来源：

CELLULAR & MOLECULAR IMMUNOLOGY | 2020年 / 17卷 / 11期

基金：

湖南省自然科学基金; 中国国家自然科学基金; 中国博士后科学基金;

关键词：

Innate immunity; ISG12a; Wnt/beta-catenin signaling pathway; PD-L1; Cancer immunity; HEPATITIS-C VIRUS; CHECKPOINT BLOCKADE; STEM-CELLS; T-CELLS; INTERFERON; RESISTANCE; BETA; EMT; METASTASIS; APOPTOSIS;

D O I：

10.1038/s41423-020-00549-9

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

The ability to harness innate immunity is a promising solution for improving cancer immunotherapy. Interferon (IFN) induces expression of IFN-stimulated genes (ISGs) by activating the JAK-STAT signaling pathway to promote innate immunity and inhibit malignant tumor growth, but the functions and mechanisms of most ISGs in cancer regulation are unknown. As an innate immune effector, ISG12a promotes the innate immune response to viral infection. In this study, ISG12a was found to be expressed at low levels in gastrointestinal cancer, represented by hepatocellular cancer (HCC) and gastric cancer (GC), and it identified as a tumor suppressor that affects clinical prognosis. ISG12a silencing accelerated the malignant transformation and epithelial-mesenchymal transition of cancer cells. Mechanistically, ISG12a promoted beta-catenin proteasomal degradation by inhibiting the degradation of ubiquitinated Axin, thereby suppressing the canonical Wnt/beta-catenin signaling pathway. Notably, beta-catenin was identified as a transcription factor forPD-L1. Inhibition of Wnt/beta-catenin signaling by ISG12a suppressed expression of the immune checkpoint PD-L1, rendering cancer cells sensitive to NK cell-mediated killing. This study reveals a mechanism underlying the anticancer effects of IFN. Some ISGs, as represented by ISG12a, may be useful in cancer therapy and prevention. The identified interrelations among innate immunity, Wnt/beta-catenin signaling, and cancer immunity may provide new insight into strategies that will improve the efficiency of immunotherapy.

引用

页码：1163 / 1179

页数：17

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