Proteomic identification of stress-response heat shock protein markers associated with tumor recurrence in patients with hepatocellular carcinoma

Abstract

Background Hepatocellular carcinoma (HCC) is one of the most deadly cancers worldwide. Surgical resections have been considered the most effective curative treatment for the disease, but the prognosis for patients after hepatic resection has remained unsatisfactory because of an extremely high recurrence rate. Reliable cancer markers to differentiate patients who are at high-risk for early recurrence would be beneficial for better post-operative management of HCC patients. Patients & Methods A total of 64 patients diagnosed with HCC(n = 22 recurrence <1 year; n = 42, 1-year disease-free) at the QueenMary Hospital (Pokfulam, Hong Kong) were included in this study.Fresh snap-frozen tumor tissues resected from HCC were subjectedto 2-DE PAGE analysis (Luk JM et al, Proteomics 2005 & 2006).Differential proteomic expression profiles between the two HCCgroups were analyzed by biomarker wizard analysis. Receiver operat-ing characteristic (ROC) curve was analyzed for each potential bio-marker candidate to determine the cut-off point for discriminatingthe HCC recurrence (R) and disease-free (DF) groups, where the area under curve (AUC) was >0.70.Results Among the total 1433 protein spots in the HCC proteome,four markers in the tumor tissues were identified in significant cor-relation with HCC recurrence by statistical analysis. By tandem MS/MS analysis, all of the four protein species were suggested to bestress-response heat shock protein (Hsp) species, including Hsp27,Hsp70 and GRP78, with the sensitivity and specificity for recurrenceat 71.4%/73.7%, 95.2%/90.9%, and 95.2%/63.6%, respectively. In addition, GRP78 in tumor tissue was positively correlated to tumor stage (r = 0.253, p < 0.05), tumor size (r = 0.247, p < 0.05) and venous infiltration (r = 0.247, p < 0.05).Conclusion The present findings indicated that patients with increased expression of Hsp markers in HCC were associated with tumor recurrence and poor prognostic values with respect to venous infiltration, tumor size and stage. Frequent monitoring of disease progression in this particular group of patients may be necessary for better clinical management.(Supported by research grants council of Hong Kong: N_HKU718/03; HKU 7320/02M)