Loss of hepatic FTCD promotes lipid accumulation and hepatocarcinogenesis by upregulating PPARγ and SREBP2
Siying Wang,
Yangyang Zhou,
Ruobing Yu,
Jing Ling,
Botai Li,
Chen Yang,
Zhuoan Cheng,
Ruolan Qian,
Zhang Lin,
Chengtao Yu,
Jiaojiao Zheng,
Xingling Zheng,
Qi Jia,
Wei Wu,
Qiangxin Wu,
Mengnuo Chen,
Shengxian Yuan,
Wei Dong,
Yaoping Shi,
Robin Jansen,
Chen Yang,
Yujun Hao,
Ming Yao,
Wenxin Qin,
Haojie Jin
Affiliations
Siying Wang
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Yangyang Zhou
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Ruobing Yu
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Jing Ling
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Botai Li
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Chen Yang
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Zhuoan Cheng
Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Ruolan Qian
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Zhang Lin
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Chengtao Yu
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Jiaojiao Zheng
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Xingling Zheng
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Qi Jia
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Wei Wu
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Qiangxin Wu
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Mengnuo Chen
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Shengxian Yuan
The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
Wei Dong
Department of Pathology, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
Yaoping Shi
Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Robin Jansen
Division of Molecular Carcinogenesis, Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands
Chen Yang
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Pharmaceutical Co. Ltd., Nanjing, China
Yujun Hao
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Ming Yao
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Wenxin Qin
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Corresponding authors. Addresses: State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, No.25, Lane 2200 Xie-Tu Road, 200032 Shanghai, China. Tel.: 021-68371092, 021-68371105.
Haojie Jin
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Corresponding authors. Addresses: State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, No.25, Lane 2200 Xie-Tu Road, 200032 Shanghai, China. Tel.: 021-68371092, 021-68371105.
Background & Aims: Exploiting key regulators responsible for hepatocarcinogenesis is of great importance for the prevention and treatment of hepatocellular carcinoma (HCC). However, the key players contributing to hepatocarcinogenesis remain poorly understood. We explored the molecular mechanisms underlying the carcinogenesis and progression of HCC for the development of potential new therapeutic targets. Methods: The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) and Genotype-Tissue Expression (GTEx) databases were used to identify genes with enhanced expression in the liver associated with HCC progression. A murine liver-specific Ftcd knockout (Ftcd-LKO) model was generated to investigate the role of formimidoyltransferase cyclodeaminase (FTCD) in HCC. Multi-omics analysis of transcriptomics, metabolomics, and proteomics data were applied to further analyse the molecular effects of FTCD expression on hepatocarcinogenesis. Functional and biochemical studies were performed to determine the significance of loss of FTCD expression and the therapeutic potential of Akt inhibitors in FTCD-deficient cancer cells. Results: FTCD is highly expressed in the liver but significantly downregulated in HCC. Patients with HCC and low levels of FTCD exhibited worse prognosis, and patients with liver cirrhosis and low FTCD levels exhibited a notable higher probability of developing HCC. Hepatocyte-specific knockout of FTCD promoted both chronic diethylnitrosamine-induced and spontaneous hepatocarcinogenesis in mice. Multi-omics analysis showed that loss of FTCD affected fatty acid and cholesterol metabolism in hepatocarcinogenesis. Mechanistically, loss of FTCD upregulated peroxisome proliferator-activated receptor (PPAR)γ and sterol regulatory element–binding protein 2 (SREBP2) by regulating the PTEN/Akt/mTOR signalling axis, leading to lipid accumulation and hepatocarcinogenesis. Conclusions: Taken together, we identified a FTCD-regulated lipid metabolic mechanism involving PPARγ and SREBP2 signaling in hepatocarcinogenesis and provide a rationale for therapeutically targeting of HCC driven by downregulation of FTCD. Impact and implications: Exploiting key molecules responsible for hepatocarcinogenesis is significant for the prevention and treatment of HCC. Herein, we identified formimidoyltransferase cyclodeaminase (FTCD) as the top enhanced gene, which could serve as a predictive and prognostic marker for patients with HCC. We generated and characterised the first Ftcd liver-specific knockout murine model. We found loss of FTCD expression upregulated peroxisome proliferator-activated receptor (PPAR)γ and sterol regulatory element–binding protein 2 (SREBP2) by regulating the PTEN/Akt/mTOR signalling axis, leading to lipid accumulation and hepatocarcinogenesis, and provided a rationale for therapeutic targeting of HCC driven by downregulation of FTCD.
