Polysialylated NCAM represses E-cadherin-mediated cell-cell adhesion in pancreatic tumor cells.
OBJECTIVE
Inhibition of cell-cell adhesion between epithelial cells represents an early step during tumor metastasis. Down-regulation or perturbation of E-cadherin-mediated adherens junctions is an essential requirement in this process.


METHODS
The interaction between polysialylated neural cell adhesion molecule (PSA-NCAM) and the E-cadherin adhesion complex was studied by coimmunoprecipitation assays. The presence of PSA-NCAM was correlated with tumor invasion by using cell-cell aggregation and cell migration assays. The importance of polysialic acid (PSA) in the interaction of NCAM with E-cadherin and inhibition of cell-cell adhesion was confirmed by enzymatic removal of PSA from NCAM and down-regulation of PSA-transferases by siRNA.


RESULTS
Expression of oncogenic K-Ras(V12) in pancreatic carcinoma cells resulted in induction of PSA-NCAM expression and reduced E-cadherin-mediated cellular adhesion. The association of PSA-NCAM with the E-cadherin adhesion complex correlated with decreased cell-cell aggregation and elevated cell migration of pancreatic carcinoma cells. Enzymatic removal of PSA from NCAM or reduction of polysialyltransferase expression led to reduced association between NCAM and E-cadherin and subsequently increased E-cadherin-mediated cell-cell aggregation and reduced cell migration.


CONCLUSIONS
Our data suggest the induction of PSA-NCAM by oncogenic K-Ras as a novel molecular mechanism by which E-cadherin-mediated cellular adhesion is reduced and dissemination of tumor cells is facilitated.
Schreiber
Susanne C
SC
Institute of Zoology 2, University Karlsruhe, Karlsruhe, Germany.
Giehl
Klaudia
K
Kastilan
Caroline
C
Hasel
Cornelia
C
Mühlenhoff
Martina
M
Adler
Guido
G
Wedlich
Doris
D
Menke
Andre
A
D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D039842:Neural Cell Adhesion Molecule L1 / Q000096:biosynthesis / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012334:RNA, Neoplasm / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012794:Sialic Acids / Q000096:biosynthesis / Q000235:genetics*; D012799:Sialyltransferases / Q000096:biosynthesis / Q000235:genetics
D015820:Cadherins; D039842:Neural Cell Adhesion Molecule L1; D012334:RNA, Neoplasm; D012794:Sialic Acids; C103469:polysialyl neural cell adhesion molecule; C046778:CMP-N-acetylneuraminate-poly-alpha-2,8-sialosyl sialyltransferase; D012799:Sialyltransferases; C515117:ST8SIA4 protein, human