Cholesterol overload in the liver aggravates oxidative stress-mediated DNA damage and accelerates hepatocarcinogenesis

Abstract

Primary liver cancers represent the second leading cause of cancer-related deaths worldwide. Diverse etiological factors include chronic viral hepatitis, aflatoxin and alcohol exposure as well as aberrant liver lipid overload. Cholesterol has been identified as a key inducer of metabolic impairment, oxidative stress and promoter of cellular dysfunction. The aim of this work was to address the oxidative stress-mediated DNA damage induced by cholesterol overload, and its role in the development of hepatocellular carcinoma.C57BL/6 male mice were fed with a high cholesterol diet, followed by a single dose of N-diethylnitrosamine (DEN, 10 μg/g, ip). Reactive oxygen species generation, DNA oxidation, antioxidant and DNA repair proteins were analyzed at different time points. Diet-induced cholesterol overload caused enhanced oxidative DNA damage in the liver and was associated with a decrease in key DNA repair genes as early as 7 days. Interestingly, we found a cell survival response, induced by cholesterol, judged by a decrement in Bax to Bcl2 ratio. Importantly, N-acetyl-cysteine supplementation significantly prevented DNA oxidation damage. Furthermore, at 8 months after DEN administration, tumor growth was significantly enhanced in mice under cholesterol diet in comparison to control animals. Together, these results suggest that cholesterol overload exerts an oxidative stress-mediated effects and promotes the development of liver cancer.

Overexpression of Hepatocyte Chemerin-156 Lowers Tumor Burden in a Murine Model of Diethylnitrosamine-Induced Hepatocellular Carcinoma

“…Concordantly, cholesterol concentrations were elevated in human HCC [68]. Cholesterol increases oxidative stress and DNA damage, and thus contributes to HCC growth [69]. In the present study, cholesterol was higher in the tumors of all animals.…”

“…In the present study, cholesterol was higher in the tumors of all animals. SREBP-2 is an important transcription factor enhancing cholesterol biosynthesis [69,70], but its active form was not changed in the tumors. ApoA1 protein was strongly diminished in the cancer tissues, and this illustrates that cholesterol accumulation may, in part, result from impaired reverse cholesterol transport [70].…”

Emodin Sensitizes Hepatocellular Carcinoma Cells to the Anti-Cancer Effect of Sorafenib through Suppression of Cholesterol Metabolism

“…Cholesterol, as an essential component for lipid raft microdomains in the cellular membrane, is important for cancer growth and aggressiveness and for maintaining oncogenic growth signaling through the PI3K-AKT and STAT3 pathways [ 20 , 30 , 31 , 32 , 33 ]. Experimental or clinical evidence has previously shown that high levels of blood cholesterol accelerate hepatocarcinogenesis and lead to poor clinical outcomes in patients with HCC [ 30 , 31 ].…”

“…Cholesterol, as an essential component for lipid raft microdomains in the cellular membrane, is important for cancer growth and aggressiveness and for maintaining oncogenic growth signaling through the PI3K-AKT and STAT3 pathways [ 20 , 30 , 31 , 32 , 33 ]. Experimental or clinical evidence has previously shown that high levels of blood cholesterol accelerate hepatocarcinogenesis and lead to poor clinical outcomes in patients with HCC [ 30 , 31 ]. Indeed, the anti-cancer and anti-metastatic effects of cholesterol-lowering drugs, such as simvastatin, lovastatin, and pitavastatin, which are mediated through suppression of the AKT and STAT3 pathways, have been shown in HCC, renal cancer, malignant melanoma, and ovarian cancer [ 22 , 23 , 24 , 32 , 33 , 34 ].…”

Cytoglobin ameliorates the stemness of hepatocellular carcinoma via coupling oxidative‐nitrosative stress signals

“…Recombinant human manganese superoxide dismutase protein (rMnSOD) counteracts the progression of non‐alcoholic steatohepatitis (NASH) to HCC . Antioxidant N‐acetyl‐cysteine supplementation significantly prevents DNA oxidative damage from cholesterol overload in HCC tumorigenesis . Cancer stem cells (CSCs) are the crucial subpopulation of cancer cells that determine tumor initiation, self‐renewal, and heterogeneity.…”