MACC1, a newly identified key regulator of HGF-MET signaling, predicts colon cancer metastasis

• Published in: Nature medicine Vol. 15; no. 1; pp. 59 - 67
• Main Authors: Stein, Ulrike, Walther, Wolfgang, Arlt, Franziska, Schwabe, Holger, Smith, Janice, Fichtner, Iduna, Birchmeier, Walter, Schlag, Peter M
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2009; Nature Publishing Group
• Subjects: Amino Acid Sequence; Animals; Base Sequence; Biomarkers, Tumor - genetics; Biomarkers, Tumor - physiology; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma - diagnosis; Carcinoma - genetics; Carcinoma - pathology; Cell culture; Cells, Cultured; Cellular signal transduction; Colon cancer; Colonic Neoplasms - diagnosis; Colonic Neoplasms - genetics; Colonic Neoplasms - pathology; Colorectal cancer; Colorectal carcinoma; Diagnosis; Gene Expression Regulation, Neoplastic; Genes; Genes, Neoplasm - physiology; Genetic aspects; Genomics; Genotype & phenotype; Growth factors; Hepatocyte Growth Factor - genetics; Infectious Diseases; Intracellular Signaling Peptides and Proteins - genetics; Metabolic Diseases; Metastasis; Mice; Mice, Nude; Mice, SCID; Molecular Medicine; Molecular Sequence Data; Neoplasm Metastasis; Neoplasm Proteins - genetics; Neurosciences; Physiological aspects; Prognosis; Proto-Oncogene Proteins c-met - genetics; Risk factors; Signal transduction; Signal Transduction - genetics; Tumors; United States; Germany
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.1889

Early identification of individuals with colorectal cancer who are at high risk of metastasis might help guide treatment choice and improve outcome. Stein et al . now report that MACC1 , a previously undescribed gene, is a prognostic indicator of colorectal cancer and describe its role as a transcriptional regulator of MET , which encodes the hepatocyte growth factor receptor and promotes metastasis of a variety of cancers. 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.