Accelerated Carcinogenesis Following Liver Regeneration is Associated with Chronic Inflammation-induced Double-strand DNA Breaks

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 Feb 6

PMID 20133864

Citations 57

Authors

Hila Barash

Eitan R Gross

Yifat Edrei

Ezra Ella

Ariel Israel

Irit Cohen

Nathalie Corchia

Tehila Ben-Moshe

Orit Pappo

Eli Pikarsky

Daniel Goldenberg

Yosef Shiloh

Eithan Galun

Rinat Abramovitch

Affiliations

Soon will be listed here.

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide and is considered to be the outcome of chronic liver inflammation. Currently, the main treatment for HCC is surgical resection. However, survival rates are suboptimal partially because of tumor recurrence in the remaining liver. Our aim was to understand the molecular mechanisms linking liver regeneration under chronic inflammation to hepatic tumorigenesis. Mdr2-KO mice, a model of inflammation-associated cancer, underwent partial hepatectomy (PHx), which led to enhanced hepatocarcinogenesis. Moreover, liver regeneration in these mice was severely attenuated. We demonstrate the activation of the DNA damage-response machinery and increased genomic instability during early liver inflammatory stages resulting in hepatocyte apoptosis, cell-cycle arrest, and senescence and suggest their involvement in tumor growth acceleration subsequent to PHx. We propose that under the regenerative proliferative stress induced by liver resection, the genomic unstable hepatocytes generated during chronic inflammation escape senescence and apoptosis and reenter the cell cycle, triggering the enhanced tumorigenesis. Thus, we clarify the immediate and long-term contributions of the DNA damage response to HCC development and recurrence.

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