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.

Fluoride Exposure Suppresses Proliferation and Enhances Endoplasmic Reticulum Stress and Apoptosis Pathways in Hepatocytes by Downregulating Sirtuin-1

“…RT-qPCR Assay. Based on the research reported [29], approximately 100 mg of rat liver tissue from each group was repeatedly ground, and AML12 cells from each group were collected separately. Total RNAs were isolated from the samples with TRIzol (TAKARA; cat.…”

Targeting Hypoxia-Inducible Factor-1α for the Management of Hepatocellular Carcinoma

“…However, as tumors outgrow their blood supply over time, chronic hypoxia develops, with paradoxical adaptive cellular responses through the stabilization of HIFs and the resumption of transcriptional activation of genes involved in angiogenesis, cellular proliferation, and cell survival [20,36,37]. The upregulation of HIF-1α and VEGF in the setting of chronic hypoxia was observed in a preclinical study of HCC rat models, resulting in tumor growth [38,39]. Additionally, upregulating the expression of anti-apoptotic genes, such as B-cell lymphoma 2 (Bcl-2), desensitizes HCC cells to apoptosis [19,25].…”

Atomic Force Microscopy and High-Resolution Spectrophotometry for Study of Anoxemia and Normoxemia in Model Experiment In Vitro

“…Hypoxemia and its consequences should also be considered when treating patients using gases such as helium, xenon, and CO 2 [ 25 , 26 , 27 ]. Intermittent hypoxemia is a special situation [ 28 ]. The morphology of RBCs, specifically the stiffness and nanostructure of their membranes, can be altered in blood diseases, resulting in impaired cellular deformability [ 29 , 30 , 31 , 32 ].…”