Chronic Intermittent Hypoxia Increases Cell Proliferation in Hepatocellular Carcinoma

Abstract

Obstructive sleep apnea (OSA) syndrome is characterized by chronic intermittent hypoxia and is associated with an increased risk of all-cause mortality, including cancer mortality. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, characterized by increasing incidence and high mortality. However, the link between HCC and OSA-related chronic intermittent hypoxia remains unclear. Herein, we used a diethylnitrosamine (DEN)-induced HCC model to investigate whether OSA-related chronic intermittent hypoxia has an impact on HCC progression. To elucidate the associated mechanisms, we first evaluated the hypoxia status in the DEN-induced HCC model. Next, to simulate OSA-related intermittent hypoxia, we exposed cirrhotic rats with HCC to intermittent hypoxia during six weeks. We performed histopathological, immunohistochemical, RT-qPCR, and RNA-seq analysis. Chronic DEN injections strongly promoted cell proliferation, fibrosis, disorganized vasculature, and hypoxia in liver tissue, which mimics the usual events observed during human HCC development. Intermittent hypoxia further increased cell proliferation in DEN-induced HCC, which may contribute to an increased risk of HCC progression. In conclusion, our observations suggest that chronic intermittent hypoxia may be a factor worsening the prognosis of HCC.

Keywords

• obstructive sleep apnea syndrome
• intermittent hypoxia
• DEN-induced rat model
• hepatocellular carcinoma
• cell proliferation