Increased expression of stathmin and elongation factor 1α in precancerous nodules with telomere dysfunction in hepatitis B viral cirrhotic patients

Ei Yong Ahn,Jeong Eun Yoo,Jee San Lee,Young Nyun Park,Hyungjin Rhee,Junjeong Choi,Jung Eun Ko,Myung Soo Kim

doi:10.1186/1479-5876-12-154

Abstract

BackgroundTelomere dysfunction is important in carcinogenesis, and recently, stathmin and elongation factor 1α (EF1α) were reported to be up-regulated in telomere dysfunctional mice.MethodsIn the present study, the expression levels of stathmin and EF1α in relation to telomere length, telomere dysfunction-induced foci (TIF), γ-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, EF1α, γ-H2AX, and p21WAF1/CIP1 were detected by immunohistochemistry.ResultThe expressions of stathmin and EF1α 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 EF1α mRNA expression did not show such a difference. The protein expressions of stathmin and EF1α 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). EF1α 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 EF1α histoscores (but not mRNA levels), were positively correlated with telomere shortening and γ-H2AX labeling index (all, P < 0.05). EF1α 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 EF1α histoscore (all, P < 0.05).ConclusionStathmin and EF1α 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 EF1α 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.

Highlights

Telomere dysfunction is important in carcinogenesis, and recently, stathmin and elongation factor 1α (EF1α) were reported to be up-regulated in telomere dysfunctional mice
Stathmin and EF1α are suggested to be closely related to telomere dysfunction, DNA damage, and inactivation of p21WAF1/CIP1 in hepatitis B virus (HBV)-related multistep hepatocarcinogenesis
Assessment of stathmin and EF1α 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

Summary

Introduction

Telomere dysfunction is important in carcinogenesis, and recently, stathmin and elongation factor 1α (EF1α) were reported to be up-regulated in telomere dysfunctional mice. Hepatocellular carcinoma (HCC) is reported as the fifth most common cancer worldwide and the third most common cause of cancer-related deaths [1]. Hepatocarcinogenesis is a multistep process, and has been characterized as the progressive accumulation of genetic and molecular changes in chronic liver disease, which leads to the production of monoclonal populations of dysplastic or transformed hepatocytes. Mutations that impair the DNA damage response pathways facilitate the survival of dysplastic cells with shortened and dysfunctional telomeres, leading to the proliferation of cells with dicentric chromosomes and the accumulation of genomic instability due to breakage-fusion-bridge cycles. Chromosomal instability is characteristic of hepatitis B virus (HBV)-related hepatocarcinogenesis [2]. A soil for HCC, is characterized by an increase in dysplastic hepatocytes that form dysplastic foci or dysplastic nodules (DNs). While DNs are considered precancerous lesions of HCC [3], various natural outcomes of DNs have been reported [4,5]

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