Upregulation of BRCA1 and BRCA2 in Human Alcoholic Hepatitis and Nonalcoholic Steatohepatitis

Abstract

Introduction: Breast cancer 1 early onset (BRCA1) and breast cancer 2 early onset (BRCA2) genes are important DNA repair genes involved in maintenance of genome stability. BRCA1 and BRCA2 gene mutations play a role in the breast cancer pathogenesis, as well as increase risk of ovarian, fallopian tube, prostate, and pancreatic tumors, and malignant melanoma. The changes of BRCA1 and BRCA2 gene expression pathways are examined in the present study of human alcoholic hepatitis (AH) and nonalcoholic steatohepatitis (NASH), especially where cell cycle arrest is involved. Method and results: RNA-sequencing (RNA-seq) in human archived formalin-fixed, paraffin-embedded (FFPE) liver tissues of AH patients showed a 12-fold upregulation of BRCA1 and 7-fold upregulation of BRCA2. Real-time PCR confirmed the increased transcript expression of BRCA1 (25-fold up) in liver tissue of AH patients. Expression of BRCA2 was 7-fold up. Immunohistochemical staining of BRCA1 and BRCA2 demonstrated that BRCA1 expression was increased in the cytoplasm of hepatocytes in AH patients (180% compared to control, P < .001). BRCA2 expression was also increased (226%, P < .001). The changes of BRCA1 and BRCA2 expression in NASH patients were 179% (P < .001) and 182% (P < .001), respectively. Furthermore, the increase of BRCA2 expression was a significant difference between AH and NASH (226% vs 182%, P < .001). Conclusion: The present data showed for the first time the upregulation of BRCA1 and BRCA2 in liver tissues from both AH and NASH patients. This suggested that BRCA1 and BRCA2 play an important role in the pathogenesis in AH and NASH, especially in the regeneration and inhibition due to cell cycle arrest.