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Abstract #2332

Chronic Liver Inflammation-Induced Double-Strand DNA Breaks Enhance Hepatocarcinogenesis

Hila Barash1, Eitan Gross2, Natalie Corchia1, Irit Cohen1, Daniel Goldenberg1, Eithan Galun1, Rinat Abramovitch1,3

1Goldyne Savad Institute for Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel; 2Pediatric Surgery, Hadassah Hebrew University Medical Center, Jerusalem, Israel; 3MRI/MRS lab HBRC, Hadassah Hebrew University Medical Center, Jerusalem, Israel

Hepatocellular-carcinoma (HCC) is the third leading cause of cancer mortality and considered to be the outcome of chronic liver inflammation. Surgical-resection is the preferred treatment for HCC; however, survival rates are suboptimal due to tumor recurrence. Our objective was to understand the molecular mechanisms linking liver regeneration under chronic-inflammation to tumorigenesis. Mdr2-knockout mice, had undergone partial-hepatectomy, and experienced enhanced hepatocarcinogenesis. Yet, liver regeneration was severely attenuated. The inflamed livers had elevated levels of double-stranded DNA breaks resulting in hepatocyte apoptosis and cell-cycle arrest. We propose that under the proliferative stress, the genomic-unstable-hepatocytes reenter the cell cycle, causing the enhanced tumorigenesis.