Reduced beta-catenin and peroxisome proliferator-activated receptor-gamma expression levels are associated with colorectal cancer metastatic progression: correlation with tumor-associated macrophages, cyclooxygenase 2, and patient outcome.
Recent studies have reported cross talk between beta-catenin, peroxisome proliferator-activated receptor-gamma, and cyclooxygenase 2 signaling pathways. We examined whether molecular changes of these pathways could be related to colorectal cancer metastatic progression. Seventy-two sporadic colorectal cancers and the distant nonneoplastic mucosa were analyzed for beta-catenin, peroxisome proliferator-activated receptor-gamma, cyclooxygenase 2, and nuclear factor kappaB levels by immunohistochemistry and Western blot. The expression profiles were correlated with patient outcome and 5-year survival. Nuclear beta-catenin staining was detected in only 18.1% of tumors and correlated with poor survival as compared with cases showing cytosolic/membrane accumulation (59.7%, P < .05). This latter group and tumor samples showing cytosolic/nuclear peroxisome proliferator-activated receptor-gamma expression (70.8%) were significantly associated with a favorable prognosis (P < .001). Remarkably, reduction or loss of beta-catenin (22.2%) and peroxisome proliferator-activated receptor-gamma (29.2%) expression was strongly correlated with marked infiltration of tumor-associated macrophages (P < .01), presence of liver metastases, and very short survival (P = .0001). Moreover, beta-catenin and peroxisome proliferator-activated receptor-gamma levels were inversely correlated with cyclooxygenase 2 (P < .01) and nuclear factor kappaB expression (P < .05). Our results suggest that reduced expression of beta-catenin and peroxisome proliferator-activated receptor-gamma could play a key role in aggressive colorectal cancer behavior. This finding may provide a relevant prognostic tool and contribute to early identification of patients at high risk of mortality.
Pancione
Massimo
M
Department of Biological and Environmental Sciences, University of Sannio, 82100 Benevento, Italy.
Forte
Nicola
N
Sabatino
Lina
L
Tomaselli
Eugenio
E
Parente
Domenico
D
Febbraro
Antonio
A
Colantuoni
Vittorio
V
D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis; D015153:Blotting, Western; D015179:Colorectal Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008264:Macrophages / Q000276:immunology*; D008297:Male; D016328:NF-kappa B / Q000096:biosynthesis; D009362:Neoplasm Metastasis / Q000473:pathology; D009367:Neoplasm Staging; D047495:PPAR gamma / Q000096:biosynthesis*; D011379:Prognosis; D051176:beta Catenin / Q000096:biosynthesis*
D014408:Biomarkers, Tumor; D016328:NF-kappa B; D047495:PPAR gamma; D051176:beta Catenin; D051546:Cyclooxygenase 2