MACC1, a newly identified key regulator of HGF-MET signaling, predicts colon cancer metastasis.
We identified a previously undescribed gene associated with colon cancer by genome-wide expression analysis in primary and metastatic carcinomas: metastasis-associated in colon cancer-1, MACC1. MACC1 expression in tumor specimens is an independent prognostic indicator of metastasis formation and metastasis-free survival. We show that the gene encoding the hepatocyte growth factor (HGF) receptor, MET, is a transcriptional target of MACC1. MACC1 promotes proliferation, invasion and HGF-induced scattering of colon cancer cells in cell culture and tumor growth and metastasis in mouse models. These phenotypes are lost in cells expressing MACC1 mutants lacking the SH3 domain or the proline-rich motif. For clinical practice, MACC1 will be useful for the identification of poor prognosis subjects with colorectal cancer and is a promising new target for intervention in metastasis formation.
Stein
Ulrike
U
Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, Berlin, Germany.
Walther
Wolfgang
W
Arlt
Franziska
F
Schwabe
Holger
H
Smith
Janice
J
Fichtner
Iduna
I
Birchmeier
Walter
W
Schlag
Peter M
PM
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000502:physiology; D002277:Carcinoma / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology*; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics*; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D015534:Trans-Activators
D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; C575027:MACC1 protein, mouse; D009363:Neoplasm Proteins; D015534:Trans-Activators; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met