Quantitative cell signalling analysis reveals down-regulation of MAPK pathway activation in colorectal cancer.

Hdl Handle:
http://hdl.handle.net/10147/127609
Title:
Quantitative cell signalling analysis reveals down-regulation of MAPK pathway activation in colorectal cancer.
Authors:
Gulmann, Christian; Sheehan, 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.ie
Citation:
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 pathology
Issue Date:
Aug-2009
URI:
http://hdl.handle.net/10147/127609
DOI:
10.1002/path.2561
PubMed ID:
19396842
Abstract:
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:
Article
Language:
en
MeSH:
Aged; Aged, 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
ISSN:
1096-9896

Full metadata record

DC FieldValue Language
dc.contributor.authorGulmann, Christianen
dc.contributor.authorSheehan, Katherine Men
dc.contributor.authorConroy, Ronán Men
dc.contributor.authorWulfkuhle, Julia Den
dc.contributor.authorEspina, Virginiaen
dc.contributor.authorMullarkey, Michelle Jen
dc.contributor.authorKay, Elaine Wen
dc.contributor.authorLiotta, Lance Aen
dc.contributor.authorPetricoin, Emanuel Fen
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-

Related articles on PubMed

All Items in Lenus, The Irish Health Repository are protected by copyright, with all rights reserved, unless otherwise indicated.