Molecular mechanisms of ethanol-associated oro-esophageal squamous cell carcinoma

Abstract

Alcohol drinking is a major etiological factor of oro-esophageal squamous cell carcinoma (OESCC). Both local and systemic effects of ethanol may promote carcinogenesis, especially among chronic alcoholics. However, molecular mechanisms of ethanol-associated OESCC are still not well understood. In this review, we summarize current understandings and propose three mechanisms of ethanol-associated OESCC: (1) Disturbance of systemic metabolism of nutrients: during ethanol metabolism in the liver, systemic metabolism of retinoids, zinc, iron and methyl groups is altered. These nutrients are known to be associated with the development of OESCC. (2) Disturbance of redox metabolism in squamous epithelial cells: when ethanol is metabolized in oro-esophageal squamous epithelial cells, reactive oxygen species are generated and produce oxidative damage. Meanwhile, ethanol may also disturb fatty-acid metabolism in these cells. (3) Disturbance of signaling pathways in squamous epithelial cells: due to its physico-chemical properties, ethanol changes cell membrane fluidity and shape, and may thus impact multiple signaling pathways. Advanced molecular techniques in genomics, epigenomics, metabolomics and microbiomics will help us elucidate how ethanol promotes OESCC.

PAX9 regulates squamous cell differentiation and carcinogenesis in the oro‐oesophageal epithelium

“…Acetaldehyde, an ethanol metabolite, is believed to be a carcinogen that contributes to the development of ESCC. Genetic polymorphisms of genes involved in ethanol metabolism, such as those encoding acetaldehyde dehydrogenase and alcohol dehydrogenase, are also strongly and consistently associated with OESCC [, ]. Our data showed that ethanol exposure caused a time‐dependent and dose‐dependent decrease in PAX9 expression in oesophageal epithelial cells in vitro (supplementary material, Figure S4).…”

Heterogeneous impact of alcohol consumption according to treatment method on survival in head and neck cancer: A prospective study

“…The background mechanisms behind the association behind alcohol drinking and survival of all HNSCC patients remain unclear, however, several mechanisms appear plausible for alcohol drinking and prognosis. First, several molecular effects of ethanol are proposed, including enhanced cell proliferation and altered expression of cytokeratin suggesting inhibition of squamous cell differentiation, interference with DNA repair machinery and DNA synthesis, and impaired antioxidant defense and enhanced production of reactive oxygen species . A second possible explanation is that alcohol consumption impairs patients’ nutrient status and immune system, leading to the inability to destroy cancer cells .…”

Endogenous Generation of Singlet Oxygen and Ozone in Human and Animal Tissues: Mechanisms, Biological Significance, and Influence of Dietary Components

“…Moreover, since ethanol is metabolized to acetaldehyde, there are increased blood levels of acetaldehyde after alcohol consumption [ 158 ] and this may promote production of ROS. Alcohol consumption is also associated with oroesophageal squamous cell carcinoma, gastric cancer, and colorectal cancer, which may be partly due to induction of ROS production by ethanol or its metabolite, acetaldehyde [ 159 – 161 ].…”