Reelin protects from colon pathology by maintaining the intestinal barrier integrity and repressing tumorigenic genes

Abstract

We previously reported that reelin, an extracellular matrix protein first known for its key role in neuronal migration, reduces the susceptibility to dextran sulphate sodium (DSS)-colitis. The aim of the current study was to determine whether reelin protects from colorectal cancer and how reelin defends from colon pathology. In the colon of wild-type and of mice lacking reelin (reeler mice) we have analysed the: i) epithelium cell renewal processes, ii) morphology, iii) Sox9, Cdx2, Smad5, Cyclin D1, IL-6 and IFNγ mRNA abundance in DSS-treated and untreated mice, and iv) development of azoxymethane/DSS-induced colorectal cancer, using histological and real time-PCR methodologies. The reeler mutation increases colitis-associated tumorigenesis, with increased tumours number and size. It also impairs the intestinal barrier because it reduces cell proliferation, migration, differentiation and apoptosis; decreases the number and maturation of goblet cells, and expands the intercellular space of the desmosomes. The intestinal barrier impairment might explain the increased susceptibility to colon pathology exhibited by the reeler mice and is at least mediated by the down-regulation of Sox9 and Cdx2. In response to DSS-colitis, the reeler colon increases the mRNA abundance of IL-6, Smad5 and Cyclin D1 and decreases that of IFNγ, conditions that might result in the increased colitis-associated tumorigenesis found in the reeler mice. In conclusion, the results highlight a role for reelin in maintaining intestinal epithelial cell homeostasis and providing resistance against colon pathology.

Identification of differentially expressed genes regulated by methylation in colon cancer based on bioinformatics analysis

“…However, there has been no study on the correlation between GDNF methylation and the prognosis of colon cancer. RELN has been reported to play a critical role in maintaining epithelial cell ho-meostasis and protecting the colon from pathological processes[44]. Furthermore, RELN is epigenetically regulated by methylation in gastric cancer[45], pancreatic cancer[46], hepatocellular cancer[47], and myeloma[48].…”

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

“…We previously reported that reelin absence increases colitis severity and colon tumorigenesis in mice [ 19 , 20 ] and that reelin was upregulated in the colon of a mouse model of acute colitis and downregulated in human colon adenocarcinoma [ 19 , 21 ]. These reelin changes were the opposite of those in DNMT-1 expression and activity, which, via the hypomethylation of the reelin promoter in acute colitis and hypermethylation in colon adenocarcinoma, increases or represses reelin expression, respectively [ 19 , 21 ].…”

Reelin levels in inflammatory bowel disease: A case-control study

“…Mutual interactions between the epithelium and the underlying basement membrane regulate proliferation, migration, differentiation, apoptosis, morphogenesis, tissue repair, inflammation, and immune response [31]. Many receptors have been identified for cellextracellular matrix molecules in intestinal epithelial cells, many of which are integrins [32]. However, the nature of cell-basement membrane interactions and their intracellular processing is largely undefined.…”

“…Studies show that Reelin deficiency is associated with bipolar disorder and major depression, autism, epilepsy, and schizophrenia [27][28][29][30]. There are also studies suggesting that Reelin may play a role in inflammatory bowel diseases [31][32][33]. Additionally, studies show its function in crypto-villus homeostasis and that Reelin regulation plays a protective role against diseases such as acute colitis [31,34].…”