Abstract
BackgroundNidogens are highly conserved proteins of basement membranes. Two nidogen proteins, nidogen 1 and nidogen 2, are known in mammals.ResultsWe show that CpG islands of both NID1 and NID2 genes are aberrantly methylated in human cancer samples and cancer cell lines. For both genes, methylation was correlated with loss of gene transcription in human cell lines. Furthermore, demethylation of the NID1 and NID2 promoters restored gene transcription, demonstrating that methylation was responsible for silencing nidogen genes. In primary tumors, we detected NID1 promoter methylation in 67% of colon cancer samples and in 90% of gastric cancers. NID2 promoter was methylated in 29% of colon and 95% of gastric cancers. Immuno-staining for nidogen-2 confirmed the correlation between aberrant methylation and loss of nidogen expression also in primary tumors, implying that aberrant methylation was a mechanism for inhibiting nidogens expression in human gastrointestinal tumors.ConclusionThese results suggest that loss of nidogens expression has a potential pathogenetic role in colon and stomach tumorigenesis. Nidogens are believed to connect laminin and collagen IV networks, hence stabilizing the basement membrane structure. Nidogens are also important for cell adhesion, as they establish contacts with various cellular integrins. Loss of nidogen expression may favor invasion and metastasis of cancer cells by loosening cell interaction with basal membrane and by weakening the strength of the basement membrane itself, first barrier from the connective vascularized matrix.
Highlights
Nidogens are highly conserved proteins of basement membranes
Human cancer cell lines are methylated at the NID1 and NID2 promoters We detected NID1 as a gene reactivated by treatment with the demethylating agent zebularine in the human cancer cell line MDA-MB-231
To confirm that reactivation was induced by promoter demethylation, we analyzed the methylation status of the NID1 promoter in the MDA-MB-231 cell line and in several other human cell lines
Summary
Nidogens are highly conserved proteins of basement membranes. Its main components include collagen IV, laminins, heparan sulfate proteoglycan (perlecan) and nidogens. It can be found under sheets of epithelial and endothelial cells and surrounding muscle, fat and muscle cells. It is essential for tissue compartmentalization and maintenance of cell phenotypes; it supplies stimuli for tissue development and remodeling [1,2]. Nidogen binds and forms ternary complex with collagen IV and laminin, connecting the two networks and stabilizing the tri-dimensional structure of the basement membrane [3]. Nidogen serves the important role of establishing and maintaining basement membrane and tissue architecture
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