Abstract
Cholesterol mediates its proliferative and metastatic effects via the metabolite 27-hydroxycholesterol (27-HC), at least in breast and endometrial cancer. We determined the serum lipoprotein profile, intratumoral cholesterol and 27-HC levels in a cohort of patients with well-differentiated papillary thyroid carcinoma (PTC; low/intermediate and high risk), advanced thyroid cancers (poorly differentiated, PDTC and anaplastic thyroid carcinoma, ATC) and benign thyroid tumors, as well as the expression of genes involved in cholesterol metabolism. We investigated the gene expression profile, cellular proliferation, and migration in Nthy-ori 3.1 and CAL-62 cell lines loaded with human low-density lipoprotein (LDL). Patients with more aggressive tumors (high-risk PTC and PDTC/ATC) showed a decrease in blood LDL cholesterol and apolipoprotein B. These changes were associated with an increase in the expression of the thyroid’s LDL receptor, whereas 3-hydroxy-3-methylglutaryl-CoA reductase and 25-hydroxycholesterol 7-alpha-hydroxylase were downregulated, with an intratumoral increase of the 27-HC metabolite. Furthermore, LDL promoted proliferation in both the Nthy-ori 3.1 and CAL-62 thyroid cellular models, but only in ATC cells was its cellular migration increased significantly. We conclude that cholesterol and intratumoral accumulation of 27-HC promote the aggressive behavior process of PTC. Targeting cholesterol metabolism could be a new therapeutic strategy in thyroid tumors with poor prognosis.
Highlights
Cancer is a multifactorial disease that is associated with important metabolic disorders, one of which is the metabolism of cholesterol
Different forms of oxysterols have been identified; the most important are 27, 24, and 7α-hydroxycholesterol. 27-hydroxycholesterol (27-HC), which is mainly synthesized in the liver, acts as a potent suppressor of cholesterol synthesis throughout the sterol regulatory element-binding proteins (SREBPs)16. 27-HC levels are controlled by two mitochondrial enzymes, namely sterol 27-hydroxylase (CYP27A1)—which is responsible for their synthesis—and 25-hydroxycholesterol 7-alpha-hydroxylase (CYP7B1), which is responsible for their catabolism[17]
Patients with highrisk papillary thyroid carcinoma (PTC) and PDTC/anaplastic carcinoma (ATC) tumors showed lower serum cholesterol levels (3.832 ± 0.198 mmo/L, p = 0.0041 and 3.793 ± 0.245 mmo/L, p = 0.0293, respectively) compared with those with benign thyroid tumor (BTT) tumors (4.933 ± 0.207 mmo/L) and low/intermediate-risk PTC (4.581 ± 0.159 mmo/L). These changes were associated with a decrease in low-density lipoprotein (LDL) cholesterol in high-risk PTC tumor patients (1.944 ± 0.222 mmo/L, p = 0.0515) and those with dedifferentiated PDTC/ATC tumors (1.775 ± 0.083 mmo/L, p = 0.0274) compared with those with BTT (2.551 ± 0.165 mmo/L) and low/intermediate-risk patients PTC (2.293 ± 0.129 mmo/L)
Summary
Cancer is a multifactorial disease that is associated with important metabolic disorders, one of which is the metabolism of cholesterol Cholesterol molecules and their metabolites play important roles in normal cells, actively participating in the formation of cell membranes, as well as the cell cycle, and the tumoral cells require an increased supply of cholesterol. To meet these needs, these deregulated cells are able to promote two strategies cholesterol uptake from the bloodstream and de novo cholesterol biosynthesis[1,2,3,4]. The objective of this study was to analyze the associations between cholesterol, intratumoral 27-HC levels, and TC tumors’ malignancy
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