Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China.
Cancer Res. 2022 Nov 2;82(21):3987-4000. doi: 10.1158/0008-5472.CAN-21-4337.
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.
ASGR1 downregulation by DNA methylation facilitates liver tumorigenesis by increasing STAT3 phosphorylation.
肝癌的特点是生长迅速且死亡率高。在肝脏细胞中几乎特异性表达的去唾液酸糖蛋白受体 1（ASGR1）在肝癌中减少。然而，ASGR1 在肝癌中的具体功能机制尚未完全阐明。在数据库筛选的基础上，我们确定 ASGR1 是受 DNA 甲基化调控的肿瘤抑制因子。ASGR1 在肝癌中的表达下调与肿瘤大小、分级和生存相关。功能获得和缺失实验表明，ASGR1 在体内和体外均能抑制肝癌的进展。RNA 测序和质谱分析表明，ASGR1 通过与神经调节素样激酶（NLK）相互作用抑制 STAT3 的酪氨酸磷酸化。NLK 以 ATP 依赖性方式结合 STAT3 的 SH2 结构域，并与糖蛋白 130（GP130）竞争，最终抑制 GP130/JAK1 介导的 STAT3 磷酸化。ASGR1 通过与 GP130 相互作用改变 NLK 和 STAT3 的结合强度。此外，NLK 的结构域区域对于结合 STAT3 和抑制其磷酸化至关重要。综上所述，这些结果证实 ASGR1 通过促进 NLK 与 STAT3 的结合并抑制 STAT3 磷酸化来抑制肝癌的进展，表明激活 ASGR1-NLK 轴的方法可能是该疾病的一种潜在治疗策略。
DNA 甲基化下调 ASGR1 可通过增加 STAT3 磷酸化促进肝肿瘤发生。
