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.