Molecular Basis of Alcohol-Related Gastric and Colon Cancer

Abstract

Many meta-analysis, large cohort studies, and experimental studies suggest that chronic alcohol consumption increases the risk of gastric and colon cancer. Ethanol is metabolized by alcohol dehydrogenases (ADH), catalase or cytochrome P450 2E1 (CYP2E1) to acetaldehyde, which is then further oxidized to acetate by aldehyde dehydrogenase (ALDH). Acetaldehyde has been classified by the International Agency for Research on Cancer (IARC) as a Group 1 carcinogen to humans. The acetaldehyde level in the stomach and colon is locally influenced by gastric colonization by Helicobacter pylori or colonic microbes, as well as polymorphisms in the genes encoding tissue alcohol metabolizing enzymes, especially ALDH2. Alcohol stimulates the uptake of carcinogens and their metabolism and also changes the composition of enteric microbes in a way to enhance the aldehyde level. Alcohol also undergoes chemical coupling to membrane phospholipids and disrupts organization of tight junctions, leading to nuclear translocation of β-catenin and ZONAB, which may contributes to regulation of genes involved in proliferation, invasion and metastasis. Alcohol also generates reactive oxygen species (ROS) by suppressing the expression of antioxidant and cytoprotective enzymes and inducing expression of CYP2E1 which contribute to the metabolic activation of chemical carcinogens. Besides exerting genotoxic effects by directly damaging DNA, ROS can activates signaling molecules involved in inflammation, metastasis and angiogenesis. In addition, alcohol consumption induces folate deficiency, which may result in aberrant DNA methylation profiles, thereby influencing cancer-related gene expression.

Specific nutritional infections early in life as risk factors for human colon and breast cancers several decades later

“…Presently it is impossible, however, to exclude additional infections by antigenically different BMMF types later in life and other inflammatory events (e.g., resulting from the microbiome, high alcohol consumption, or linked to obesity). 77,80 They seem to play, at best, a very minor role in this process and would create substantial difficulties in explaining the previously discussed findings, correlated with colon and breast cancers.…”

“…It has also been reported to play a significant role as the molecular basis of alcohol-related gastric and colon cancers. 80 Specific micro-RNAs are upregulated in inflammation and cancers: these accounts for miR-21, miR-155 and miR-210. [81][82][83][84] MiRNAs have been identified in bovine milk.…”

Non‐invasive metastasis prognosis from plasma metabolites in stage II colorectal cancer patients: The DACHS study

“…Interestingly, the potential to degrade PEG in humans by alcohol dehydrogenase (ADH) is long known 55 and ADH activity was recently linked to gastric and colon cancer. 56 Hence, we speculate that differences in PEG degradation between patients are linked to risk of metastasis formation. However, to validate this hypothesis further studies are necessary.…”

Alcohol consumption is associated with glaucoma severity regardless of ALDH2 polymorphism

“…enzymes, microsomal proteins, and microtubules) and forming adducts with DNA, which ultimately results in impaired target-organ function 21,22 , ALDH2′s acetaldehyde-removal activity has attracted clinical interest. The genetic diversity of ALDH2, on chromosome 12, is well established elsewhere 2,17,[23][24][25] . The G-to-A missense mutation in exon 12, where glutamate at position 504 is replaced by lysine (Glu504Lys), is one of the representative SNPs (rs671) in ALDH2.…”