The Goldyne Savad Institute of Gene Therapy, Magnetic Resonance Imaging/Magnetic Resonance Spectroscopy Laboratory, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2207-12. doi: 10.1073/pnas.0908867107. Epub 2010 Jan 25.
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.
肝细胞癌（HCC）是全球癌症死亡的第三大主要原因，被认为是慢性肝脏炎症的结果。目前，HCC 的主要治疗方法是手术切除。然而，由于剩余肝脏中的肿瘤复发，生存率并不理想。我们的目的是了解将慢性炎症下的肝脏再生与肝肿瘤发生联系起来的分子机制。Mdr2-KO 小鼠是一种与炎症相关的癌症模型，接受了部分肝切除术（PHx），这导致了肝癌的发生增强。此外，这些小鼠的肝再生受到严重抑制。我们证明了在早期肝脏炎症阶段，DNA 损伤反应机制的激活和基因组不稳定性增加导致了肝实质细胞凋亡、细胞周期停滞和衰老，并表明它们参与了 PHx 后肿瘤生长的加速。我们提出，在肝切除引起的再生性增殖应激下，慢性炎症期间产生的基因组不稳定的肝细胞逃避衰老和凋亡并重新进入细胞周期，引发增强的肿瘤发生。因此，我们阐明了 DNA 损伤反应对 HCC 发展和复发的即时和长期贡献。
