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BRCA1‐Mediated DNA Damage Response is a Potential Player Involved in Mallory‐Denk Body (MDB) Formation in Alcoholic Hepatitis (AH)
Author(s) -
Liu Hui,
French Barbara,
Li Jun,
Tillman Brittany,
French Samuel
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.766.1
Subject(s) - alcoholic hepatitis , cancer research , cell cycle , biology , dna damage , alcoholic liver disease , microbiology and biotechnology , cell cycle checkpoint , gene , rna , dna , medicine , genetics , cirrhosis
The mechanisms involved in chronic liver diseases that progress to hepatocellular carcinoma (HCC) are multifactorial. Mallory‐Denk Bodies (MDBs) are a major component of chronic liver diseases. They are prevalent in various hepatic diseases such as alcoholic hepatitis (AH), non‐alcoholic steatohepatitis (NASH) and HCC. However, the mechanism of MDB formation is still poorly understood. In this study, RNA sequencing (RNA‐seq) was used to explore the overall gene expression profile in human archived formalin‐fixed, paraffin‐embedded (FFPE) liver tissues of AH patients who had formed MDBs. It was found that the breast cancer 1 protein (BRCA1), which is a tumor suppressor involved in basic cellular functions necessary for cell replication and DNA synthesis, has a 12‐fold up regulation induction in AH biopsies with MDBs present. This indicates a crucial role played by this gene. The prominent elevated mRNA expression of p21 (Cip1) was also discovered in this series. This may suggest that MDB formation can induce the increase of p21 expression through BRCA1‐mediated DNA damage response, resulting in the arrest of cell cycle progression. Cell cycle arrest is possibly a potential mechanism for liver MDB formation. Similar to p21, the downstream molecule E2F of the BRCA1 pathway was significantly up regulated, indicating an altered modulation of G1/S phase transition in AH patients. Interestingly, miR‐483, which can target BRCA1 mRNA expression, was found to be a 2‐fold down regulated in this array. These data highlight that BRCA1‐mediated DNA damage response may play an essential role in MDB formation in AH. The up regulation of BRCA1 mRNA may be regulated by miR‐483.