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

Yi-Kang Wang; Ning Ma; Sheng Xu; Jing-Yi Huang; Qian-Zhi Ni; Hui-Jun Cao; Qian-Wen Zheng; Bing Zhu; Ji Xia; Feng-Kun Zhang; Xu-Fen Ding; Xiao-Song Qiu; Tian-Wei Chen; Kang Wang; Wei Chen; Zhi-Gang Li; Shu-Qun Cheng; Dong Xie; Jing-Jing Li

doi:10.1016/j.celrep.2023.112340

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

Cell Rep. 2023 Apr 25;42(4):112340. doi: 10.1016/j.celrep.2023.112340. Epub 2023 Apr 5.

Authors

Yi-Kang Wang¹, Ning Ma², Sheng Xu¹, Jing-Yi Huang¹, Qian-Zhi Ni³, Hui-Jun Cao¹, Qian-Wen Zheng⁴, Bing Zhu¹, Ji Xia¹, Feng-Kun Zhang¹, Xu-Fen Ding¹, Xiao-Song Qiu⁴, Tian-Wei Chen⁵, Kang Wang⁶, Wei Chen⁷, Zhi-Gang Li⁸, Shu-Qun Cheng⁶, Dong Xie⁹, Jing-Jing Li¹⁰

Affiliations

¹ CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
² CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Department of Thoracic Surgery, Section of Esophageal Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
³ CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200433, China.
⁴ CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
⁵ CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
⁶ Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200433, China.
⁷ Institute of Clinical Medicine Research, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou 310014, China.
⁸ Department of Thoracic Surgery, Section of Esophageal Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
⁹ CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; NHC Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing 100022, China. Electronic address: dxie@sibs.ac.cn.
¹⁰ CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; NHC Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing 100022, China. Electronic address: tide7@163.com.

PMID: 37027301
DOI: 10.1016/j.celrep.2023.112340

Abstract

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 the decreased PPDPF expression indicates poor prognosis. In the dimethylnitrosamine (DEN)-induced HCC mouse model, hepatocyte-specific depletion of Ppdpf promotes hepatocarcinogenesis, and reintroduction of PPDPF into liver-specific Ppdpf knockout (LKO) mice inhibits the accelerated HCC development. Mechanistic study shows that PPDPF regulates nuclear factor κB (NF-κB) signaling through modulation of RIPK1 ubiquitination. PPDPF interacts with RIPK1 and facilitates K63-linked ubiquitination of RIPK1 via recruiting the E3 ligase TRIM21, which catalyzes K63-linked ubiquitination of RIPK1 at K140. In addition, liver-specific overexpression of PPDPF activates NF-κB signaling and attenuates apoptosis and compensatory proliferation in mice, which significantly suppresses HCC development. This work identifies PPDPF as a regulator of NF-κB signaling and provides a potential therapeutic candidate for HCC.

Keywords: CP: Cancer; HCC; NF-κB; PPDPF; RIPK1; TRIM21; apoptosis; compensatory proliferation; ubiquitination.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinogenesis / genetics
Carcinoma, Hepatocellular* / metabolism
Liver Neoplasms* / pathology
Mice
NF-kappa B / metabolism
Ubiquitination

Substances

NF-kappa B
PPDPF protein, mouse
SS-A antigen
Ripk1 protein, mouse