Asialoglycoprotein Receptor 1 Functions as a Tumor Suppressor in Liver Cancer via Inhibition of STAT3

癌症研究 肝癌 糖蛋白130 癌变 磷酸化 车站3 癌症 生物 DNA甲基化 酪氨酸磷酸化 细胞生物学 基因表达 生物化学 基因 遗传学 肝细胞癌
作者
Xingxin Zhu,Guangyuan Song,Shiyu Zhang,Jun Chen,Xiaoyi Hu,Hai Zhu,Xing Jia,Zequn Li,Wenfeng Song,Jian Chen,Cheng Jin,Mengqiao Zhou,Yongchao Zhao,Haiyang Xie,Shusen Zheng,Penghong Song
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:82 (21): 3987-4000 被引量:23
标识
DOI:10.1158/0008-5472.can-21-4337
摘要

Abstract Liver cancer is characterized by aggressive growth and high mortality. Asialoglycoprotein receptor 1 (ASGR1), which is expressed almost exclusively in liver cells, is reduced in liver cancer. However, the specific mechanism of ASGR1 function in liver cancer has not been fully elucidated. On the basis of database screening, we identified ASGR1 as a tumor suppressor regulated by DNA methylation. Expression of ASGR1 was downregulated in liver cancer and correlated with tumor size, grade, and survival. Functional gain and loss experiments showed that ASGR1 suppresses the progression of liver cancer in vivo and in vitro. RNA sequencing and mass spectrometry showed that ASGR1 inhibits tyrosine phosphorylation of STAT3 by interacting with Nemo-like kinase (NLK). NLK bound the SH2 domain of STAT3 in an ATP-dependent manner and competed with glycoprotein 130 (GP130), ultimately suppressing GP130/JAK1-mediated phosphorylation of STAT3. ASGR1 altered the binding strength of NLK and STAT3 by interacting with GP130. Furthermore, the domain region of NLK was crucial for binding STAT3 and curbing its phosphorylation. Collectively, these results confirm that ASGR1 suppresses the progression of liver cancer by promoting the binding of NLK to STAT3 and inhibiting STAT3 phosphorylation, suggesting that approaches to activate the ASGR1–NLK axis may be a potential therapeutic strategy in this disease. Significance: ASGR1 downregulation by DNA methylation facilitates liver tumorigenesis by increasing STAT3 phosphorylation.
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