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

Stein U., et al. 2009. Nature med., 15(1), 59-67, Jan., 2009.

Speaker: Yu-Fen Tseng (曾鈺芬)                                   Time: 13:10~14:10, Mar. 31, 2010

Commentator: Dr. Bei-Chang Yang (楊倍昌老師)      Place: Room 601

Abstract:

Colon cancer shows high malignancy worldwide. The formation of distant metastasis is the most lethal event during the course of the carcinogenesis. It limits the success of the therapy and causes failure of the treatment¹. Hepatocyte growth factor/Scatter factor (HGF/SF) is a multifunctional growth factor which induces cell scattering, invasion, proliferation and branching morphogenesis. The c-Met receptor tyrosine kinase is the receptor for HGF/SF and mediates HGF/SF induced biological activities². Many oncogenic signaling pathways induced biological responses through Met activation, such as PI3K and Ras³. The authors analyzed colon mucosa, primary tumors, and metastatic tumors by differential display PCR and identified a novel gene, MACC1, (metastasis-associated in colon cancer-1). MACC1 was identified as a prognostic marker for colon cancer metastasis and correlated with metastasis-free survival rate by a statistic analysis (Cox regression). Nuclear MACC1 expression accompanied with high MET expression in tumors developed distant metastasis. However, in nonmetastasis tumors, MACC1 was mainly detected in the cytoplasm. They showed that expression of MACC1 but not MACC1 mutants (lacking SH3 domain or harboring an AXXA instead of a PXXP motif) in SW480 cells induces MET expression and increases cell migration, invasion, and proliferation. Expression of MACC1 induced scattering of SW480 cells after treatment with HGF. Inhibition of MEK or Akt abrogated HGF-induced scattering of SW480 cells which expressing MACC1. They also revealed that MET promoter activity is regulated by MACC1, and MACC1 bind to the MET promoter in cell lines as well in tumors. SW480 cells expressing MACC1 were subcutaneously injected into SCID mice and the tumor growth was increased. Furthermore, metastasis in the mouse liver was detected after intrasplenic transplantation of SW480 cells expressing MACC1. Collectively, MACC1 induced tumor growth and liver metastasis in mouse model. MACC1 may be a prognostic biomarker and a therapeutic target for clinical colon cancer.

References:

1.         Di Renzo, M.F. et al. Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer. Clin Cancer Res 1, 147-154 (1995).

2.         Birchmeier, C., Birchmeier, W., Gherardi, E. & Vande Woude, G.F. Met, metastasis, motility and more. Nature reviews 4, 915-925 (2003).

3.         Maulik, G. et al. Role of the hepatocyte growth factor receptor, c-Met, in oncogenesis and potential for therapeutic inhibition. Cytokine & growth factor reviews 13, 41-59 (2002).