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

21 Citations (Scopus)

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

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DNA Repair
DNA Damage
Hepatocellular Carcinoma
Fibrosis
Cyclin-Dependent Kinases
Growth
Proliferating Cell Nuclear Antigen
Fetal Proteins
Messenger RNA
Proteins
Western Blotting
Enzyme-Linked Immunosorbent Assay
DNA
Cyclin-Dependent Kinase Inhibitor p21
Genomic Instability
Nuclear Proteins
Reverse Transcriptase Polymerase Chain Reaction
Serum
Up-Regulation
Down-Regulation

Keywords

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

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

GADD45-α expression in cirrhosis and hepatocellular carcinoma : Relationship with DNA repair and proliferation. / Gramantieri, Laura; Chieco, Pasquale; Giovannini, Catia; Lacchini, Michela; Treré, Davide; Grazi, Gian Luca; Venturi, Annamaria; Bolondi, Luigi.

In: Human Pathology, Vol. 36, No. 11, 11.2005, p. 1154-1162.

Research output: Contribution to journalArticle

Gramantieri, L, Chieco, P, Giovannini, C, Lacchini, M, Treré, D, Grazi, GL, Venturi, A & Bolondi, L 2005, 'GADD45-α expression in cirrhosis and hepatocellular carcinoma: Relationship with DNA repair and proliferation', Human Pathology, vol. 36, no. 11, pp. 1154-1162. https://doi.org/10.1016/j.humpath.2005.07.017
Gramantieri, Laura ; Chieco, Pasquale ; Giovannini, Catia ; Lacchini, Michela ; Treré, Davide ; Grazi, Gian Luca ; Venturi, Annamaria ; Bolondi, Luigi. / GADD45-α expression in cirrhosis and hepatocellular carcinoma : Relationship with DNA repair and proliferation. In: Human Pathology. 2005 ; Vol. 36, No. 11. pp. 1154-1162.
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