2. Academic Validation
  3. SOCS5-RBMX stimulates SREBP1-mediated lipogenesis to promote metastasis in steatotic HCC with HBV-related cirrhosis

SOCS5-RBMX stimulates SREBP1-mediated lipogenesis to promote metastasis in steatotic HCC with HBV-related cirrhosis

  • NPJ Precis Oncol. 2024 Mar 1;8(1):58. doi: 10.1038/s41698-024-00545-6.
Youpeng Wang # 1,  Ziyin Zhao # 2,  Tingting Guo # 1,  Tiansong Wu 1,  Mao Zhang 3,  Dingan Luo 1,  Kunpeng Dou 4,  Yeni Yang 1,  Cheng Jin 5,  Bingyuan Zhang 1,  Bin Zhang 6,  Bing Han 7
Affiliations

Affiliations

  • 1 Department of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Qingdao University, Qingdao, China.
  • 2 Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
  • 3 Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 4 College of Information Science and Engineering, Ocean University of China, Qingdao, China.
  • 5 Institute of Medical Robotics, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
  • 6 Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China. 18661808021@163.com.
  • 7 Department of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Qingdao University, Qingdao, China. hanbing@qduhospital.cn.
  • # Contributed equally.
PMID: 38429411 DOI: 10.1038/s41698-024-00545-6
Abstract

Abnormal lipid metabolism promotes hepatocellular carcinoma (HCC) progression, which engenders therapeutic difficulties owing to unclear mechanisms of the phenomenon. We precisely described a special steatotic HCC subtype with HBV-related cirrhosis and probed its drivers. Hematoxylin-eosin (HE) staining of 245 HCC samples revealed a special HCC subtype (41 cases) characterized by HBV-related cirrhosis and intratumoral steatosis without fatty liver background, defined as steatotic HCC with HBV-related cirrhosis (SBC-HCC). SBC-HCC exhibits a larger tumor volume and worse prognosis than non-SBC-HCC. Screening for driver genes promoting fatty acid (FA) biosynthesis in the Gao's HBV-related cirrhosis HCC cases and GSE121248' HBV-related HCC cases revealed that high expression of SOCS5 predicts increased FA synthesis and that SOCS5 is upregulated in SBC-HCC. Through proteomics, metabolomics, and both in vivo and in vitro experiments, we demonstrated that SOCS5 induces lipid accumulation to promote HCC metastasis. Mechanistically, through co-IP and GST-pulldown experiments, we found that the SOCS5-SH2 domain, especially the Amino acids Y413 and D443, act as critical binding sites for the RBMX-RRM domain. SOCS5-RBMX costimulates the promoter of SREBP1, inducing de novo lipogenesis, while mutations in the SH2 domain, Y413, and D443 reverse this effect. These findings precisely identified SBC-HCC as a special steatotic HCC subtype and highlighted a new mechanism by which SOCS5 promotes SBC-HCC metastasis.

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