Quantitative cell signalling analysis reveals down-regulation of MAPK pathway activation in colorectal cancer.
Authors
Gulmann, ChristianSheehan, Katherine M
Conroy, Ronán M
Wulfkuhle, Julia D
Espina, Virginia
Mullarkey, Michelle J
Kay, Elaine W
Liotta, Lance A
Petricoin, Emanuel F
Affiliation
Department of Pathology, Beaumont Hospital, Dublin, Ireland. christiangulmann@beaumont.ieIssue Date
2009-08MeSH
AgedAged, 80 and over
Blotting, Western
Colorectal Neoplasms
DNA Mismatch Repair
Down-Regulation
Enzyme Activation
Female
Gene Expression Profiling
Humans
Immunohistochemistry
Isoenzymes
MAP Kinase Kinase 4
MAP Kinase Signaling System
Male
Middle Aged
Mitogen-Activated Protein Kinases
Neoplasm Staging
Oligonucleotide Array Sequence Analysis
Phosphorylation
p38 Mitogen-Activated Protein Kinases
Metadata
Show full item recordCitation
Quantitative cell signalling analysis reveals down-regulation of MAPK pathway activation in colorectal cancer. 2009, 218 (4):514-9 J. Pathol.Journal
The Journal of pathologyDOI
10.1002/path.2561PubMed ID
19396842Abstract
Mitogen-activated protein kinases (MAPK) are considered to play significant roles in colonic carcinogenesis and kinase inhibitor therapy has been proposed as a potential tool in the treatment of this disease. Reverse-phase microarray assays using phospho-specific antibodies can directly measure levels of phosphorylated protein isoforms. In the current study, samples from 35 cases of untreated colorectal cancer colectomies were laser capture-microdissected to isolate epithelium and stroma from cancer as well as normal (i.e. uninvolved) mucosa. Lysates generated from these four tissue types were spotted onto reverse-phase protein microarrays and probed with a panel of antibodies to ERK, p-ERK, p38, p-p38, p-JNK, MEK and p-MEK. Whereas total protein levels were unchanged, or slightly elevated (p38, p = 0.0025) in cancers, activated isoforms, including p-ERK, p-p38 and p-JNK, were decreased two- to four-fold in cancers compared with uninvolved mucosa (p < 0.0023 in all cases except for p-JNK in epithelium, where decrement was non-significant). This was backed up by western blotting. Dukes' stage B and C cancers displayed lower p-ERK and p-p38 expression than Dukes' stage A cancers, although this was not statistically significant. It is concluded that MAPK activity may be down-regulated in colorectal cancer and that further exploration of inhibitory therapy in this system should be carefully evaluated if this finding is confirmed in larger series.Item Type
ArticleLanguage
enISSN
1096-9896ae974a485f413a2113503eed53cd6c53
10.1002/path.2561