Abstract
Reprogramming of cellular energy metabolism, such as lipid metabolism, is a hallmark of squamous cell carcinoma of the head and neck (SCCHN). However, whether protein expression related to fatty acid oxidation (FAO) affects survival in SCCHN remains unclear. We aimed to investigate FAO-related enzyme expression and determine its correlation with clinicopathological variables in SCCHN patients. Immunohistochemical analysis (IHC) of FAO-related protein expression, including carnitine palmitoyltransferase 1 (CPT1), the acyl-CoA dehydrogenase family, and fatty acid synthase (FAS), was performed using tissue microarrays from 102 resected SCCHN tumors. Expressions were categorized according to IHC scores, and the statistical association with clinicopathological factors was determined. Moderate-to-high expression of long-chain acyl-CoA dehydrogenase (LCAD) had a protective role against cancer-related death (adjusted hazard ratio (HR), 0.2; 95% confidence interval (CI), 0.05–0.87) after covariate adjustment. Age and clinical stage remained independent predictors of survival (adjusted HR, 1.75; 95% CI, 1.22–2.49 for age; adjusted HR, 14.33; 95% CI, 1.89–108.60 for stage III/IV disease). Overexpression of medium-chain acyl-CoA dehydrogenase and FAS correlated with advanced tumor stage (T3/T4); however, none of these factors were independent predictors of survival. Several FAO-related enzymes were upregulated and LCAD overexpression had a protective effect on overall survival in advanced SCCHN patients. FAO-related-enzyme expression might have a prognostic impact on survival outcomes in SCCHN.
Highlights
Squamous cell carcinoma of the head and neck (SCCHN) is one of the leading causes of cancer-related death globally [1]
SCCHN tumors expressing a high level of phosphorylated acetyl-CoA carboxylase 1 or ACC2 are associated with decreased survival [4,5]
We examined the expressions of fatty acid synthase (FAS), an enzyme responsible for the endogenous synthesis of fatty acids, because several previous studies have shown that its overexpression was associated with poor prognosis, higher histologic grade, and nodal metastasis in SCCHN [27,28]
Summary
Squamous cell carcinoma of the head and neck (SCCHN) is one of the leading causes of cancer-related death globally [1]. One of the hallmarks of SCCHN is the reprogramming of cellular energy metabolism [2,3]. SCCHN tumors expressing a high level of phosphorylated acetyl-CoA carboxylase 1 (pACC1) or ACC2 are associated with decreased survival [4,5]. The major cellular function of ACC is to produce malonyl-CoA from acetyl-CoA for fatty acid synthesis [6]. Phosphorylation of ACC inhibits catabolic functions such as lipid storage and causes cellular metabolism to switch to fatty acid oxidation (FAO) [7]. The major enzymes involved in FAO include carnitine palmitoyltransferase (CPT), the acyl-CoA dehydrogenase family, and hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (HADHA). The acyl-CoA dehydrogenase (ACAD) family includes very-long-chain, long-chain, medium-chain, and short-chain acyl-CoA dehydrogenases (VLCAD, LCAD, MCAD, and SCAD, respectively) [9]. In addition to useful intermediates, the final product of FAO is acetyl-CoA, which enters the citric acid cycle in the mitochondrion for energy generation
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