Nidogen 1 and 2 gene promoters are aberrantly methylated in human gastrointestinal cancer.
BACKGROUND
Nidogens are highly conserved proteins of basement membranes. Two nidogen proteins, nidogen 1 and nidogen 2, are known in mammals.


RESULTS
We 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.


CONCLUSIONS
These 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.
Ulazzi
Linda
L
Dipartimento di Medicina Sperimentale e Diagnostica e Centro Interdipartimentale per la Ricerca sul Cancro, Università di Ferrara, Ferrara, Italy. lindt1978@yahoo.it
Sabbioni
Silvia
S
Miotto
Elena
E
Veronese
Angelo
A
Angusti
Angela
A
Gafà
Roberta
R
Manfredini
Stefano
S
Farinati
Fabio
F
Sasaki
Takako
T
Lanza
Giovanni
G
Negrini
Massimo
M
D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D005770:Gastrointestinal Neoplasms / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D020014:K562 Cells; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*
D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules; D004273:DNA, Neoplasm; D008562:Membrane Glycoproteins; C114729:NID2 protein, human; C029967:nidogen