Oncotarget

Research Papers: Pathology:

Aberrant modulation of the BRCA1 and G1/S cell cycle pathways in alcoholic hepatitis patients with Mallory Denk Bodies revealed by RNA sequencing

Hui Liu, Ming Gong, Barbara A. French, Guanghong Liao, Jun Li, Brittany Tillman and Samuel W. French _

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Oncotarget. 2015; 6:42491-42503. https://doi.org/10.18632/oncotarget.6382

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Abstract

Hui Liu1,*, Ming Gong2,*, Barbara A. French1, Guanghong Liao1, Jun Li1, Brittany Tillman1 and Samuel W. French1

1 Department of Pathology, LABioMed at Harbor UCLA Medical Center, Torrance, CA, USA

2 Department of Pediatrics, LABioMed at Harbor UCLA Medical Center, Torrance, CA, USA

* These authors have contributed equally to this work

Correspondence to:

Samuel W. French, email:

Keywords: liver disease, cell cycle arrest, balloon hepatocyte, p15, p21, Pathology Section

Received: June 19, 2015 Accepted: November 15, 2015 Published: November 25, 2015

Abstract

Mallory-Denk Bodies (MDBs) are prevalent in various liver diseases including alcoholic hepatitis (AH) and are formed in mice livers by feeding DDC. Liver injury from alcohol administration causes balloon hepatocytes and MDB formation impeding liver regeneration. By comparing AH livers where MDBs had formed with normal liver transcriptomes obtained by RNA sequencing (RNA-Seq), there was significant upregulation of BRCA1-mediated signaling and G1/S cell cycle checkpoint pathways. The transcriptional architecture of differentially expressed genes from AH livers reflected step-wise transcriptional changes progressing to AH. Key molecules such as BRCA1, p15 and p21 were significantly upregulated both in AH livers and in the livers of the DDC re-fed mice model where MDBs had formed. The increase of G1/S cell cycle checkpoint inhibitors p15 and p21 results in cell cycle arrest and inhibition of liver regeneration, implying that p15 and p21 could be exploited for the identification of specific targets for the treatment of liver disease. Provided here for the first time is the RNA-Seq data that represents the fully annotated catalogue of the expression of mRNAs. The most prominent alterations observed were the changes in BRCA1-mediated signaling and G1/S cell cycle checkpoint pathways. These new findings expand previous and related knowledge in the search for gene changes that might be critical in the understanding of the underlying progression to the development of AH.


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