Quantitative cell signalling analysis reveals down-regulation of MAPK pathway activation in colorectal cancer.
Sheehan, Katherine M
Conroy, Ronán M
Wulfkuhle, Julia D
Mullarkey, Michelle J
Kay, Elaine W
Liotta, Lance A
Petricoin, Emanuel F
AffiliationDepartment of Pathology, Beaumont Hospital, Dublin, Ireland. firstname.lastname@example.org
Aged, 80 and over
DNA Mismatch Repair
Gene Expression Profiling
MAP Kinase Kinase 4
MAP Kinase Signaling System
Mitogen-Activated Protein Kinases
Oligonucleotide Array Sequence Analysis
p38 Mitogen-Activated Protein Kinases
MetadataShow full item record
CitationQuantitative cell signalling analysis reveals down-regulation of MAPK pathway activation in colorectal cancer. 2009, 218 (4):514-9 J. Pathol.
JournalThe Journal of pathology
AbstractMitogen-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.
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