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

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) stai...

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Bibliographic Details
Published in:NPJ precision oncology 2024-03, Vol.8 (1), p.58-58, Article 58
Main Authors: Wang, Youpeng, Zhao, Ziyin, Guo, Tingting, Wu, Tiansong, Zhang, Mao, Luo, Dingan, Dou, Kunpeng, Yang, Yeni, Jin, Cheng, Zhang, Bingyuan, Zhang, Bin, Han, Bing
Format: Article
Language:English
Subjects:
631/67/1504/1610/4029
631/67/2327
631/67/395
Cancer Research
Gene Therapy
Human Genetics
Internal Medicine
Lipids
Liver cancer
Liver cirrhosis
Medicine
Medicine & Public Health
Metabolism
Metastasis
Oncology
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Summary: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.
ISSN:2397-768X
2397-768X
DOI:10.1038/s41698-024-00545-6