Thymosin beta 4, a potential marker of malignancy and prognosis in hepatocellular carcinoma

Background: The lack of effective early diagnostic markers is an obstacle in clinical diagnosis and treatment of hepatocellular carcinoma (HCC). Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is an increasing popular approach for identification of clinically relevant parameters including biomarkers. Patients and methods: 540 subjects, including 274 HCC, 119 liver cirrhosis, 89 hepatitis, and 58 healthy volunteers were enrolled. MALDI-TOF MS was used to select potential novel biomarkers from serum of HCC patients. Its clinical application was evaluated by experiments and clinical data analysis. Results: We identified Thymosin beta 4 (T beta 4) in serum by MALDI-TOF MS. The expression of T beta 4 was detected up-regulating in HCC cells and tissues which enhanced motility of HCC cells. More important, the level of serum T beta 4 was significantly elevated in HCC patients. The AUROC showed the optimum diagnostic cut-off was 1063.6 ng/mL, ROC and 95% CI of T beta 4 (0.908; 0.880-0.935) were larger than that of serum AFP (0.712; 0.662-0.762; p < 0.001). The sensitivity (91.3% vs 83.1%) and specificity (81.2% vs 20.3%) of serum T beta 4 were higher than alpha-fetoprotein (AFP). In AFP-negative HCC, the sensitivity could reach to 80.5%. ROC analysis showed serum T beta 4 had a better performance compared with AFP in distinguishing early-stage and small HCC. T beta 4 is correlated with TNM stage (p = 0.016) and vascular invasion (p = 0.005). Survival analysis indicated the survival time of T beta 4 positive patients was shorter (p < 0.001). Cox analysis suggested T beta 4 could be an independent factor for HCC prognosis. Conclusion: T beta 4 may serve as a novel biomarker for HCC diagnosis and prognosis.