Down-regulation of E-cadherin gene expression by collagen type I and type III in pancreatic cancer cell lines.
E-cadherin-mediated cell-cell adhesion is reduced in epithelial tumors, which is thought to be a prerequisite to acquire invasive properties. We observed that several pancreatic carcinoma cell lines with high metastatic potential expressed normal levels of E-cadherin and possessed functional E-cadherin/catenin adhesion complexes. When the cell lines PANC-1, BxPC-3, and PaTu8988s were cultured either on type I or type III collagen, E-cadherin gene expression was repressed, and E-cadherin and catenin protein concentrations were reduced. In contrast, growth on fibronectin and collagen type IV had no influence. Collagen type I- or type III-dependent reduction of E-cadherin expression led to decreased cell-cell adhesion, increased proliferation, and migratory activity as well as morphological transformation. Overexpression of activated c-Src in PANC-1 cells mimicked collagen-induced E-cadherin down-regulation and changed the elevated cell proliferation and migration. Conversely, treatment of cells with the Src-inhibitors PP1 or herbimycin A resulted in complete suppression of collagen type I-induced E-cadherin decrease. Our data demonstrate that specific collagens are able to promote metastatic behavior by down-regulation of E-cadherin gene expression in a Src-kinase-dependent manner. This points toward a novel mechanism for substrate-dependent signaling and underlines the significance of extracellular matrix environment for tumor growth and invasiveness.
Menke
A
A
Internal Medicine I, University of Ulm, D-89081 Ulm, Germany. andre.menke@medizin.uni-ulm.de
Philippi
C
C
Vogelmann
R
R
Seidel
B
B
Lutz
M P
MP
Adler
G
G
Wedlich
D
D
D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D003094:Collagen / Q000378:metabolism / Q000494:pharmacology*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039421:Integrin alpha2; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D051178:alpha Catenin; D051176:beta Catenin; D019061:src-Family Kinases / Q000378:metabolism
D015703:Antigens, CD; C495273:CTNNA1 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D016326:Extracellular Matrix Proteins; D039421:Integrin alpha2; D015534:Trans-Activators; D051178:alpha Catenin; D051176:beta Catenin; D003094:Collagen; D019061:src-Family Kinases