Studies On The Function And Potential Mechanism Of SOCS5 In Abnormal Lipid Metabolism Induced Invasion And Metastasis Of Hepatocellular Carcinoma

Objective:Hepatocellular carcinoma(HCC)is the third leading cause of cancer-related death worldwide,with more than 900,000 new cases and more than 800,000 deaths every year,seriously endangering the lives and health of people around the world.Abnormal lipid metabolism promotes the progression of HCC.In addition to providing cancer cells with more energy,fatty acid composition(saturated/unsaturated fatty acids)and abundance are closely related to membrane fluidity and protein dynamics,and can regulate tolerance to reactive oxygen species.At the same time,they form lipid rafts in the cell membrane,promoting the recruitment of signaling proteins and transducting cascades to regulate various carcinogenic processes,including tumor proliferation and invasion.However,the specific mechanisms by which hepatoma cells adapt and utilize lipids to promote malignant progression remain understood.A specific subtype of HCC in the New York and Tokyo areas of Japan has been described in past studies,characterized by "steatohepatitis" in some HCC tissues,defined as "steatohepatitis" HCC.However,there are still no reports of this subtype of HCC in China.Unlike patients with HCC in Europe,the United States and Japan,about 85% of HCC in China develops from hepatitis B-related cirrhosis.Exploring this particular subtype of abnormal lipid metabolism HCC in Chinese population and looking for driver genes related to its disease characteristics can provide guidance for targeted therapy and personalized treatment.Methods:In order to explore the specific lipid metabolism of HCC subtypes in the Chinese population,we observed HE-stained images of 245 cases of HCC tissue and described steatotic HCC with HBV-related cirrhosis(SBC-HCC)as a specific HCC subtype.In the HCC patient cohort in the TCGA dataset and the HBV-associated HCC patient cohort in Gao et al.,the lipid score of HCC patients was calculated using the lipid synthesis scoring formula.In the high-lipid group and low-lipid group,gene differential expression,random forest,Cox regression and other analysis methods were carried out to identify SOCS5 as a key disease characteristic gene.The effects of SOCS5 on lipid synthesis and HCC cell invasion and migration were explored through proteomics,transcriptomics and in vivo and in vivo experiments.Results:1.We found that SBC-HCC is a new HCC subtype in the Chinese group,which is characterized by intratumoral steatosis,HBV infection,HBV-related cirrhosis,and no fatty liver background.Compared to patients with non-SBC-HCC,we found that patients with SBC-HCC had larger tumors and shorter OS and PFS.2.In the HCC patient cohort in the TCGA dataset and the HBV-related HCC patient cohort of Gao et al.,we identified SOCS5 as one of the potential driver genes in SBC-HCC.High expression of SOCS5 predicts increased fatty acid synthesis in HCC,and SOCS5 expression is upregulated in SBC-HCC.3.Combined with proteome,metabolome,in vivo and in vitro functional analysis,we demonstrated that SOCS5 can induce SREBP1 pathway-mediated lipid production to promote HCC invasion and migration.Conclusion:We found that SBC-HCC is a specific HCC subtype in the Chinese population and describe a novel mechanism by which SOCS5 promotes SBC-HCC invasion and metastasis by stimulating de novo lipid synthesis mediated by the SREBP1 pathway.SOCS5-specific blockers may lay the groundwork for targeted therapy for SBC-HCC.