title: Increased expression of stathmin and elongation factor 1α in precancerous nodules with telomere dysfunction in hepatitis B viral cirrhotic patients.
abstract: BACKGROUND
  Telomere dysfunction is important in carcinogenesis, and recently, stathmin and elongation factor 1α (EF1α) were reported to be up-regulated in telomere dysfunctional mice.
  
  
  METHODS
  In 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.
  
  
  RESULTS
  The 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).
  
  
  CONCLUSIONS
  Stathmin 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.
authors.forename: Ei Yong
authors.initials: EY
authors.lastname: Ahn
authors.forename: Jeong Eun
authors.initials: JE
authors.lastname: Yoo
authors.forename: Hyungjin
authors.initials: H
authors.lastname: Rhee
authors.forename: Myung Soo
authors.initials: MS
authors.lastname: Kim
authors.forename: Junjeong
authors.initials: J
authors.lastname: Choi
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Ko
authors.forename: Jee San
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, 250 Seongsan-ro, Seodaemun-gu, Seoul, South Korea. young0608@yuhs.ac.
authors.forename: Young Nyun
authors.initials: YN
authors.lastname: Park
mesh_terms: D000328:Adult; D005260:Female; D006509:Hepatitis B / Q000150:complications / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020648:Peptide Elongation Factor 1 / Q000378:metabolism*; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism*; D050777:Stathmin / Q000378:metabolism*; D016615:Telomere
chemical_list: D020648:Peptide Elongation Factor 1; C493995:STMN1 protein, human; D050777:Stathmin