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dc.contributor.authorGulmann, Christian
dc.contributor.authorSheehan, Katherine M
dc.contributor.authorConroy, Ronán M
dc.contributor.authorWulfkuhle, Julia D
dc.contributor.authorEspina, Virginia
dc.contributor.authorMullarkey, Michelle J
dc.contributor.authorKay, Elaine W
dc.contributor.authorLiotta, Lance A
dc.contributor.authorPetricoin, Emanuel F
dc.date.accessioned2011-04-07T08:21:42Z
dc.date.available2011-04-07T08:21:42Z
dc.date.issued2009-08
dc.identifier.citationQuantitative cell signalling analysis reveals down-regulation of MAPK pathway activation in colorectal cancer. 2009, 218 (4):514-9 J. Pathol.en
dc.identifier.issn1096-9896
dc.identifier.pmid19396842
dc.identifier.doi10.1002/path.2561
dc.identifier.urihttp://hdl.handle.net/10147/127609
dc.description.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.
dc.language.isoenen
dc.subject.meshAged
dc.subject.meshAged, 80 and over
dc.subject.meshBlotting, Western
dc.subject.meshColorectal Neoplasms
dc.subject.meshDNA Mismatch Repair
dc.subject.meshDown-Regulation
dc.subject.meshEnzyme Activation
dc.subject.meshFemale
dc.subject.meshGene Expression Profiling
dc.subject.meshHumans
dc.subject.meshImmunohistochemistry
dc.subject.meshIsoenzymes
dc.subject.meshMAP Kinase Kinase 4
dc.subject.meshMAP Kinase Signaling System
dc.subject.meshMale
dc.subject.meshMiddle Aged
dc.subject.meshMitogen-Activated Protein Kinases
dc.subject.meshNeoplasm Staging
dc.subject.meshOligonucleotide Array Sequence Analysis
dc.subject.meshPhosphorylation
dc.subject.meshp38 Mitogen-Activated Protein Kinases
dc.titleQuantitative cell signalling analysis reveals down-regulation of MAPK pathway activation in colorectal cancer.en
dc.typeArticleen
dc.contributor.departmentDepartment of Pathology, Beaumont Hospital, Dublin, Ireland. christiangulmann@beaumont.ieen
dc.identifier.journalThe Journal of pathologyen
dc.description.provinceLeinster
html.description.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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