Chang-Il Hwanga, Andres Matosoa, David C. Corneya, Andrea Flesken-Nikitina, Stefanie Kornerb, Wei Wangc, Carla Boccacciod, Snorri S. Thorgeirssone, Paolo M. Comogliod, Heiko Hermekingb, and Alexander Yu. Nikitina,1
aDepartment of Biomedical Sciences, and
cMicroarray Core Facility, Cornell University, Ithaca, NY 14853;
bExperimental and Molecular Pathology, Institute of Pathology, The Ludwig-Maximilians University, D-80337 Munich, Germany;
dDivision of Molecular Oncology, Institute for Cancer Research and Treatment, University of Torino Medical School, 10060 Candiolo, Italy; and
eNational Cancer Institute, National Institutes of Health, Laboratory of Experimental Carcinogenesis, Center for Cancer Research, Bethesda, MD 20892
Edited* by Patricia K. Donahoe, Massachusetts General Hospital, Boston, MA, and approved July 14, 2011 (received for review November 22, 2010)
Recent observations suggest that p53 mutations are responsible not only for growth of primary tumors but also for their dissemination. However, mechanisms involved in p53-mediated control of cell motility and invasion remain poorly understood. By using the primary ovarian surface epithelium cell culture, we show that conditional inactivation of p53 or expression of its mutant forms results in overexpression of MET receptor tyrosine kinase, a crucial regulator of invasive growth. At the same time, cells acquire increased MET-dependent motility and invasion. Wild-type p53 negatively regulates MET expression by two mechanisms: (i) transactivation of MET-targeting miR-34, and (ii) inhibition of SP1 binding to MET promoter. Both mechanisms are not functional in p53 absence, but mutant p53 proteins retain partial MET promoter suppression. Accordingly, MET overexpression, cell motility, and invasion are particularly high in p53-null cells. These results identify MET as a critical effector of p53 and suggest that inhibition of MET may be an effective antimetastatic approach to treat cancers with p53 mutations. These results also show that the extent of advanced cancer traits, such as invasion, may be determined by alterations in individual components of p53/MET regulatory network.
1To whom correspondence should be addressed.
Author contributions: C.-I.H., A.M., and A.Y.N. designed research; C.-I.H., A.M., and A.F.-N. performed research; C.-I.H., D.C.C., S.K., C.B., S.S.T., P.M.C., and H.H. contributed new reagents/analytic tools; C.-I.H., A.M., W.W., and A.Y.N. analyzed data; and C.-I.H. and A.Y.N. wrote the paper.