Expression of L1-CAM and ADAM10 in human colon cancer cells induces metastasis.
L1-CAM, a neuronal cell adhesion receptor, is also expressed in a variety of cancer cells. Recent studies identified L1-CAM as a target gene of beta-catenin-T-cell factor (TCF) signaling expressed at the invasive front of human colon cancer tissue. We found that L1-CAM expression in colon cancer cells lacking L1-CAM confers metastatic capacity, and mice injected in their spleen with such cells form liver metastases. We identified ADAM10, a metalloproteinase that cleaves the L1-CAM extracellular domain, as a novel target gene of beta-catenin-TCF signaling. ADAM10 overexpression in colon cancer cells displaying endogenous L1-CAM enhanced L1-CAM cleavage and induced liver metastasis, and ADAM10 also enhanced metastasis in colon cancer cells stably transfected with L1-CAM. DNA microarray analysis of genes induced by L1-CAM in colon cancer cells identified a cluster of genes also elevated in a large set of human colon carcinoma tissue samples. Expression of these genes in normal colon epithelium was low. These results indicate that there is a gene program induced by L1-CAM in colon cancer cells that is also present in colorectal cancer tissue and suggest that L1-CAM can serve as target for colon cancer therapy.
Gavert
Nancy
N
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Sheffer
Michal
M
Raveh
Shani
S
Spaderna
Simone
S
Shtutman
Michael
M
Brabletz
Thomas
T
Barany
Francis
F
Paty
Phillip
P
Notterman
Daniel
D
Domany
Eytan
E
Ben-Ze'ev
Avri
A
D051722:ADAM Proteins / Q000096:biosynthesis* / Q000235:genetics; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis* / Q000235:genetics; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005786:Gene Expression Regulation; D045325:HCT116 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000556:secondary*; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D039842:Neural Cell Adhesion Molecule L1 / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection; D051176:beta Catenin / Q000378:metabolism
D008565:Membrane Proteins; D039842:Neural Cell Adhesion Molecule L1; D051176:beta Catenin; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human