Genomic amplification of MET with boundaries within fragile site FRA7G and upregulation of MET pathways in esophageal adenocarcinoma.
Esophageal adenocarcinoma (EA) is characterized by a poor prognosis making the identification of clinically targetable proteins essential for improving patient outcome. We report the involvement of multiple alterations of the MET pathway in EA development and progression. Microarray analysis of Barrett's metaplasia, dysplasia, and EA revealed overexpression of the MET oncogene in EAs but only those with MET gene amplification. STS-amplification mapping revealed that the boundary of the MET amplicon in these EAs is defined by fragile site FRA7G. We also identified an amplicon at 11p13 that resulted in amplification and overexpression of CD44, a gene involved in MET autophosphorylation upon HGF stimulation. Tissue microarrays with phospho-MET-specific antibodies demonstrated a uniformly high abundance of MET activation in primary EA and cells metastatic to lymph nodes but to a lesser extent in a subset of metaplastic and dysplastic Barrett's samples. Increased expression of multiple genes in the MET pathway associated with invasive growth, for example, many MMPs and osteopontin, also was found in EAs. Treatment of EA-derived cell lines with geldanamycin, an inhibitor for tyrosine kinases including MET receptor kinase, reduced cell migration and induced EA cell apoptosis. The data indicate that upregulation of the MET pathway may contribute to the poor outcome of EA patients and that therapeutic agents targeting this pathway may help improve patient survival.
Miller
C T
CT
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Lin
L
L
Casper
A M
AM
Lim
J
J
Thomas
D G
DG
Orringer
M B
MB
Chang
A C
AC
Chambers
A F
AF
Giordano
T J
TJ
Glover
T W
TW
Beer
D G
DG
D000230:Adenocarcinoma / Q000235:genetics*; D015153:Blotting, Western; D043283:Chromosome Fragile Sites; D004938:Esophageal Neoplasms / Q000235:genetics*; D005784:Gene Amplification; D006801:Humans; D047468:Immunoprecipitation; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met; D012333:RNA, Messenger / Q000235:genetics; D017978:Receptors, Growth Factor / Q000235:genetics*; D015854:Up-Regulation
D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met