A TNFR2-hnRNPK Axis Promotes Primary Liver Cancer Development via Activation of YAP Signaling in Hepatic Progenitor Cells
A TNFR2-hnRNPK Axis Promotes Primary Liver Cancer Development via Activation of YAP Signaling in Hepatic Progenitor Cells
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TNFR2-hnRNPK 轴通过激活肝祖细胞中的 YAP 信号传导促进原发性肝癌的发展。
DOI：
10.1158/0008-5472.can-20-3175
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发表时间：
2021-06-01
期刊：
影响因子：
11.2
通讯作者：
Wei, Lixin
中科院分区：
文献类型：
--
作者：
Meng, Yan;Zhao, Qiudong;Wei, Lixin
大多数原发性肝癌（PLC）病例的进展主要是由于潜在的慢性肝脏炎症，但炎症介导的PLC的潜在机制仍不清楚。在这里，我们发现了肿瘤坏死因子受体II（TNFR 2）-hnRNPK-YAP信号轴在肝祖细胞（HPC）PLC的发展至关重要。TNF α诱导的雅普活化在HPC恶性转化和肝肿瘤发生过程中需要TNFR 2，而不是TNF受体I（TNFR 1）。从机制上讲，异质核核糖核蛋白K（hnRNPK）作用于TNF α-TNFR 2信号传导的下游，直接与全基因组靶基因启动子上的雅普相互作用并稳定YAP，从而共同调节雅普靶基因的表达。单细胞RNA测序证实TNFR 2-hnRNPK与雅普表达和HPC的病理重要性相关。因此，肿瘤坏死因子受体2、hnRNPK和雅普的表达在肝癌组织中均上调，并且与包括患者存活率在内的肝癌预后不良密切相关。总的来说，这项研究阐明了肿瘤坏死因子受体在HPC介导的肿瘤发生的不同作用，揭示了TNF α介导的炎症环境和雅普激活的HPC在PLC development.Significance：这项工作定义了如何hnRNPK连接TNF α信号和海马通路转录共激活因子雅普在肝祖细胞在原发性肝肿瘤发生。
Most primary liver cancer (PLC) cases progress mainly due to underlying chronic liver inflammation, yet the underlying mechanisms of inflammation-mediated PLC remain unclear. Here we uncover a TNF receptor II (TNFR2)-hnRNPK-YAP signaling axis in hepatic progenitor cells (HPC) essential for PLC development. TNFR2, but not TNF receptor I (TNFR1), was required for TNF alpha-induced activation of YAP during malignant transformation of HPCs and liver tumorigenesis. Mechanistically, heterogeneous nuclear ribonuclear protein K (hnRNPK) acted downstream of TNF alpha-TNFR2 signaling to directly interact with and stabilize YAP on target gene promoters genome-wide, therefore coregulating the expression of YAP target genes. Single-cell RNA sequencing confirmed the association of TNFR2-hnRNPK with YAP expression and the pathologic importance of HPC. Accordingly, expressions of TNFR2, hnRNPK, and YAP were all upregulated in PLC tissues and were strongly associated with poor prognosis of PLC including patient survival. Collectively, this study clarifies the differential roles of TNFRs in HPC-mediated tumorigenesis, uncovering a TNFR2-hnRNPK-centered mechanistic link between the TNF alpha-mediated inflammatory milieu and YAP activation in HPCs during PLC development.Significance: This work defines how hnRNPK links TNF alpha signaling and Hippo pathway transcription coactivator YAP in hepatic progenitor cells during primary liver tumorigenesis.