ABSTRACT: BACKGROUND: Telomere dysfunction is important in carcinogenesis, and recently, stathmin and elongation factor 1? (EF1?) were reported to be up-regulated in telomere dysfunctional mice. METHODS: In the present study, the expression levels of stathmin and EF1? in relation to telomere length, telomere dysfunction-induced foci (TIF), ?-H2AX, and p21WAF1/CIP1 expression were assessed in specimens of hepatitis B virus (HBV)-related multistep hepatocarcinogenesis, including 13 liver cirrhosis specimens, 14 low-grade dysplastic nodules (DN), 17 high-grade DNs, and 14 hepatocellular carcinomas (HCC). Five normal liver specimens were used as controls. TIF were analyzed by telomere fluorescent in situ hybridization (FISH) combined with immunostaining, while the protein expressions of stathmin, EF1?, ?-H2AX, and p21WAF1/CIP1 were detected by immunohistochemistry. RESULT: The expressions of stathmin and EF1? gradually increased as multistep hepatocarcinogenesis progressed, showing the highest levels in HCC. Stathmin mRNA levels were higher in high-grade DNs than normal liver and liver cirrhosis, whereas EF1? mRNA expression did not show such a difference. The protein expressions of stathmin and EF1? were found in DNs of precancerous lesions, whereas they were absent or present at very low levels in normal liver and liver cirrhosis. Stathmin histoscores were higher in high-grade DNs and low-grade DNs than in normal liver (all, P<0.05). EF1? histoscores were higher in high-grade DNs than in normal liver and liver cirrhosis (all, P<0.05). Stathmin mRNA levels and histoscores, as well as EF1? histoscores (but not mRNA levels), were positively correlated with telomere shortening and ?-H2AX labeling index (all, P<0.05). EF1? histoscores were also positively correlated with TIF (P<0.001). Significantly greater inactivation of p21WAF1/CIP1 was observed in low-grade DNs, high-grade DNs, and HCC, compared to liver cirrhosis (all, P<0.05). p21WAF1/CIP1 labeling index was inversely correlated with TIF, stathmin mRNA level, and EF1? histoscore (all, P<0.05). CONCLUSION: Stathmin and EF1? are suggested to be closely related to telomere dysfunction, DNA damage, and inactivation of p21WAF1/CIP1 in HBV-related multistep hepatocarcinogenesis. Accordingly, assessment of stathmin and EF1? levels as a reflection of telomere dysfunction may be helpful in evaluating the biological characteristics of precancerous hepatic nodules in hepatitis B viral cirrhotic patients.
