Reelin Protects against Colon Pathology via p53 and May Be a Biomarker for Colon Cancer Progression

Simple Summary Colon cancer is a multifactorial disease involving genetic, environmental and lifestyle risk factors. Despite being one of the most common malignancies and a leading cause of cancer-related death worldwide, its underlying molecular mechanisms are scarcely known, highlighting the need to identify novel biomarkers for the clinical detection of its initiation and progression. The aim of the current study was to elucidate the role of the protein reelin in colon cancer initiation and progression using mouse models and human samples that extend from colitis or precancerous lesions to colon cancer. The results might contribute to understanding the mechanisms involved in colon cancer, and suggest that reelin may be a biomarker of colon pathology progression. Previous observations made in human and mouse colons suggest that reelin protects the colon from pathology. In this study, we evaluated reelin expression during the transition from either colitis or precancerous lesions to colon cancer and tried to elucidate reelin regulation under these transition processes. Samples of healthy and pathological colons from humans and mice treated with either azoxymethane/dextran sulfate sodium (DSS) or azoxymethane alone were used. The relative abundances of reelin, DNMT-1 and ApoER2 mRNAs were determined by PCR in the colon samples cited above and in the tissue adjacent to mouse colon polyps and adenocarcinomas. In both, humans and mice, reelin mRNA abundance increased significantly in ulcerative colitis and slightly in polyps and decreased in adenomas and adenocarcinomas. Reelin expression was higher in the tissue adjacent to the colon adenocarcinoma and lower in the lesion itself. The reelin expression changes may result, at least in part, from those in DNMT-1 and appear to be independent of ApoER2. Lack of reelin downregulated p-Akt and p53 in healthy colon and prevented their increases in the inflamed colon, whereas it increased GSK-3 beta in DSS-untreated mice. In conclusion, reelin mRNA abundance depends on the severity of the colon pathology, and its upregulation in response to initial injuries might prevent the beginning of colon cancer, whereas reelin repression favors it. Increased p53 expression and activation may be involved in this protection. We also propose that changes in colon reelin abundance could be used to predict colon pathology progression.

Automated summary

Colon cancer is a complex disease with various genetic, environmental, and lifestyle risk factors. This study investigated the role of the protein reelin in the initiation and progression of colon cancer using both mouse models and human samples. The results suggest that reelin may serve as a potential biomarker for predicting the progression of colon pathology, and its dysregulation may contribute to the development of colon cancer. These findings provide valuable insights into the molecular mechanisms of colon cancer and could have implications for its diagnosis and treatment.