Primary Study On Primary Hepatocellular Carcinoma-Specific Serum Cytokines

BackgroundHepatocellular carcinoma(HCC)is one of the most destructive cancers in the world,with the characteristics of easy recurrence and metastasis,and a very poor clinical prognosis.Traditional treatment methods mainly include surgical resection,interventional therapy,targeted therapy or liver transplantation,etc.Patients with advanced hepatocellular carcinoma(HCC)usually have poor prognosis.Early detection,early diagnosis and active and effective treatment of HCC can significantly improve the survival rate of patients.Cirrhosis,as an early lesion of liver cancer,Currently,there is still a lack of effective non-invasive serum diagnostic markers for the transformation of liver cirrhosis to HCC.AFP,as a traditional serum marker of liver cancer,has low sensitivity and specificity,especially for the detection of early liver cancer.Therefore,actively seeking and detecting related serum cytokines is expected to be an ideal diagnostic method.ObjectiveTo identify the hepatocellular carcinoma(HCC)-specific cytokines with differential expressionby profiling serum levels of 507 cytokines using cytokine array in patients with HCC,cirrhosis,hepatitis and healthy controls.MethodsSerum cytokines in non-cancer control and HCC patients were profiled by cytokine antibody microarray.Enrichment of KEGG biological pathways was analyzed by DAVID and the makeup of biological functions was analyzed by Proteo Map.After construction of a protein-protein interaction network based on differentially expressed cytokines,the "degrees" and "betweennesses" of the node molecules were calculated to identify the key cytokines associated with HCC,which were validated by ELISA.Results1.Among the 507 cytokines,a total of 43 HCC-related cytokines with differential expression ratio greater than 1.5 were identified,including 26 cytokines with high and 17 cytokines with low expression,respectively;2.Forty-three differentially expressed cytokines were involved in multiple biological pathways,among which VEGFA was the most involved,followed by TGFB3.3.Proteomap analysis showed that 80% of the differentially expressed cytokines were involved in various signaling pathways,such as JAK-STAT signaling pathway,RAS signaling pathway,MAPK signaling pathway,etc.4.In the protein-protein interaction network composed of differentially expressed cytokines,the top 5 cytokines with "Degree" and "Betweenness" score included VEGFA,VCAM1,CXCR4,CCR7 and TLR3;5.ELLSA results showed that the expressions of VEGFA,CCR7 and CXCR4 in serum of HCC patients were significantly higher than those of healthy controls.The expression of VEGFA in serum of patients with chronic hepatitis B was higher than that of patients with cirrhosis and healthy controls.There was no significant difference in the expression of CCR7 and CXCR4 in serum of patients with chronic hepatitis B and cirrhosis.ConclusionVEGFA,CCR7 and CXCR4 were preliminarily considered as potential serum markers of HCC,but further studies are needed to confirm this.