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

Abstract

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.

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Figure 1: MACC1 cDNA and translated protein sequence.
Figure 2: MACC1 expression in primary, not-yet-metastasized tumors has importance for metastasis development and metastasis-free survival of subjects with colon cancer.
Figure 3: MACC1, but no MACC1 domain mutants, induces expression of the receptor tyrosine kinase MET and causes increased cell motility and proliferation in vitro.
Figure 4: HGF-induced scattering and growth depend on expression and nuclear translocation of MACC1.
Figure 5: Promoter activity of the HGF receptor tyrosine kinase MET is regulated by MACC1.
Figure 6: MACC1 increases tumor growth and metastasis in mice.

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GenBank/EMBL/DDBJ

Protein Data Bank

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Acknowledgements

We thank M. Niederstrasser, K.-D. Wernecke and D. Brett for support on bioinformatics and biostatistics. We thank W. Haensch and C. Röcken for pathohistological evaluation of the tumors and I. Wendler for management of the tumor bank. We thank S. Habedank for immunohistochemistry of the tumors. We are grateful to H. Kalthoff and S. Haye for performing the orthotopic transplantation experiments, to D. Kobelt and U. Sack for performing the in vivo imaging and to W. Haider for carrying out the animal histopathology. We thank I. Kelch for generating the SW620 clones expressing MACC1 shRNA. We also thank Y. Liu (University of Pittsburgh) for providing us with the MET promoter constructs and C. Daly (Dublin City University) for designing the MACC1 siRNAs. We are thankful to R.H. Shoemaker, U. Schaeper and M. Becker for scientific discussions. The excellent technical assistance of M. Lemm, C. Fleuter, P. Hermann, L. Malcherek, A. Kopacek, J. Aumann, L. Bauer and C. Röefzaad is gratefully acknowledged. We are grateful to R. Hodge for critically reading the manuscript. This work was supported by a grant from the Wilhelm-Sander-Foundation, Germany.

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Correspondence to Ulrike Stein.

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Stein, U., Walther, W., Arlt, F. et al. MACC1, a newly identified key regulator of HGF-MET signaling, predicts colon cancer metastasis. Nat Med 15, 59–67 (2009). https://doi.org/10.1038/nm.1889

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