GADD45-α expression in cirrhosis and hepatocellular carcinoma: Relationship with DNA repair and proliferation

Laura Gramantieri, Pasquale Chieco, Catia Giovannini, Michela Lacchini, Davide Treré, Gian Luca Grazi, Annamaria Venturi, Luigi Bolondi

Research output: Contribution to journalArticle

Abstract

Growth arrest and DNA damage 45-α (GADD45-α) is a nuclear protein involved in maintenance of genomic stability, DNA repair, and suppression of cell growth through interaction with nuclear elements, including cyclin-dependent kinase inhibitor 1A (CDKN1A) and PCNA. In this study, GADD45-α expression was assessed in 28 cases of hepatocellular carcinoma (HCC) and matched cirrhosis tissues, and correlated with the presence of DNA-bound PCNA and CDKN1A as markers of DNA repair, as well as with clinicopathologic variables including histopathologic grade, tumor size, nodularity, viral status, α-fetoprotein serum levels, and p53 and Ki67 immunostaining. GADD45-α and CDKN1A messenger RNA (mRNA) were analyzed by reverse transcriptase-polymerase chain reaction. GADD45-α protein expression was evaluated by Western blot (WB) and enzyme-linked immunosorbent assays (ELISAs). PCNA and CDKN1A DNA-bound fractions were determined by WB. GADD45-α mRNA was down-regulated in 20 of 26 HCCs with respect to matched cirrhosis, but no correlation was found with the corresponding protein levels assessed by both WB and ELISA. GADD45-α and CDKN1A protein levels were related to each other both in cirrhotic and in neoplastic tissues, and a concordant up- or down-regulation was observed in HCCs with respect to cirrhosis. DNA-bound PCNA and CDKN1A were present in 5 HCCs and were associated with higher GADD45-α protein levels assessed by ELISA. No significant association was found in HCCs between GADD45-α protein expression and histopathologic grading, nodule size, focality, and proliferation, whereas a positive correlation was found with α-fetoprotein serum levels. In conclusion, GADD45-α mRNA was down-regulated with respect to matched cirrhosis in most HCCs; however, no correlation was found between mRNA and protein levels. GADD45-α protein levels were higher in HCCs with DNA-bound CDKN1A and PCNA, suggesting a possible role in DNA repair.

Original languageEnglish
Pages (from-to)1154-1162
Number of pages9
JournalHuman Pathology
Volume36
Issue number11
DOIs
Publication statusPublished - Nov 2005

Keywords

  • CDKN1A
  • Cell proliferation
  • DNA repair
  • GADD45-α
  • HCC
  • PCNA

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Gramantieri, L., Chieco, P., Giovannini, C., Lacchini, M., Treré, D., Grazi, G. L., Venturi, A., & Bolondi, L. (2005). GADD45-α expression in cirrhosis and hepatocellular carcinoma: Relationship with DNA repair and proliferation. Human Pathology, 36(11), 1154-1162. https://doi.org/10.1016/j.humpath.2005.07.017