2. Academic Validation
  3. HDLBP promotes hepatocellular carcinoma proliferation and sorafenib resistance by suppressing Trim71-dependent RAF1 degradation

HDLBP promotes hepatocellular carcinoma proliferation and sorafenib resistance by suppressing Trim71-dependent RAF1 degradation

  • Cell Mol Gastroenterol Hepatol. 2022 Oct 13;S2352-345X(22)00216-8. doi: 10.1016/j.jcmgh.2022.10.005.
Jingsheng Yuan 1,  Tao Lv 1,  Jian Yang 1,  Zhenru Wu 2,  Lvnan Yan 1,  Jiayin Yang 3,  Yujun Shi 4,  Li Jiang 5
Affiliations

Affiliations

  • 1 Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu 610041, China; Laboratory of Liver Transplantation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu 610041, China.
  • 2 Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital of Sichuan University, Chengdu 610041, China.
  • 3 Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu 610041, China; Laboratory of Liver Transplantation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu 610041, China. Electronic address: doctoryjy@scu.edu.cn.
  • 4 Laboratory of Liver Transplantation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu 610041, China; Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital of Sichuan University, Chengdu 610041, China. Electronic address: shiyujun@scu.edu.cn.
  • 5 Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu 610041, China; Laboratory of Liver Transplantation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu 610041, China. Electronic address: jl339@126.com.
PMID: 36244648 DOI: 10.1016/j.jcmgh.2022.10.005
Abstract

Background & aims: The contribution of abnormal metabolic targets to hepatocellular carcinoma (HCC) progression and the associated regulatory mechanisms are attractive research areas. High-density lipoprotein binding protein (HDLBP) is an important transporter that protects cells from excessive Cholesterol accumulation, but few studies have identified a role for HDLBP in HCC progression.

Methods: HDLBP expression was determined in HCC tissues and published datasets. The biological roles of HDLBP in vitro and in vivo were examined by performing a series of functional experiments.

Results: An integrated analysis confirmed that HDLBP expression was significantly elevated in HCC compared to noncancerous liver tissues. The knockdown or overexpression of HDLBP substantially inhibited or enhanced, respectively, HCC proliferation and sorafenib resistance. Subsequently, a mass spectrometry screen identified RAF1 as a potential downstream target of HDLBP. Mechanistically, when RAF1 was stabilized by HDLBP, MEKK1 continuously induced RAF1Ser259-dependent MAPK signalling. Meanwhile, HDLBP interacted with RAF1 by competing with the TRIM71 E3 Ligase and inhibited RAF1 degradation through the ubiquitin-proteasome pathway.

Conclusions: Our study reveals that HDLBP is an important mediator that stabilizes the RAF1 protein and maintains its activity, leading to HCC progression and sorafenib resistance. Thus, HDLBP might represent a potential biomarker and future therapeutic target for HCC.

Keywords

MEKK1; tripartite motif containing 71; ubiquitination; vigilin.

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