PPDPF suppresses the development of hepatocellular carcinoma through TRIM21-mediated ubiquitination of RIPK1

Pancreatic progenitor cell differentiation and proliferation factor (PPDPF) has been reported to play a role in tumorigenesis. However, its function in hepatocellular carcinoma (HCC) remains poorly understood. In this study, we report that PPDPF is significantly downregulated in HCC and indicats poor prognosis and survival for HCC patients. In the DEN-induced HCC mouse model, hepatocyte-specific depletion of Ppdpf promots hepatocarcinogenesis, and reintroduction of PPDPF into LKO mice inhibits the accelerated HCC development. Mechanistic study reveals that PPDPF regulated NF-kB signaling through modulation of RIPK1 ubiquitination. PPDPF interacts with RIPK1 and facilitates K63-linked ubiquitination of RIPK1 via recruiting the E3 ligase TRIM21, which catalyzs K63-linked ubiquitination of RIPK1 on K140. In addition, liver-specific overexpression of PPDPF activats NF-kB signaling, attenuats apoptosis and compensatory proliferation in mice, which significantly suppresses HCC development. This work identifies PPDPF as a regulator of NF-kB signaling and provides a potential therapeutic candidate for HCC.

胰腺祖细胞分化增殖因子（Pancreatic progenitor cell differentiation and proliferation factor, PPDPF）已有研究表明其参与肿瘤发生过程，但其在肝细胞癌（hepatocellular carcinoma, HCC）中的功能仍未得到充分阐释。本研究发现，PPDPF在肝细胞癌组织中显著下调，且与肝细胞癌患者的不良预后及生存期缩短密切相关。在二乙基亚硝胺（diethylnitrosamine, DEN）诱导的肝细胞癌小鼠模型中，肝细胞特异性敲除Ppdpf可促进肝细胞癌变；而向LKO小鼠中重新导入PPDPF，则可抑制其加速的肝细胞癌发生进程。机制研究揭示，PPDPF通过调控受体相互作用蛋白激酶1（receptor-interacting serine/threonine-protein kinase 1, RIPK1）的泛素化修饰，调节核因子κB（nuclear factor kappa-B, NF-κB）信号通路。PPDPF可与RIPK1相互结合，并通过招募E3泛素连接酶TRIM21，促进RIPK1发生K63位泛素化修饰；其中TRIM21可催化RIPK1第140位赖氨酸残基上的K63泛素化。此外，在小鼠体内实现肝脏特异性过表达PPDPF可激活NF-κB信号通路，减轻细胞凋亡及代偿性增殖，从而显著抑制肝细胞癌的发生发展。本研究明确了PPDPF作为NF-κB信号通路调控因子的身份，并为肝细胞癌治疗提供了潜在的候选靶点。