摘要
Multiple lines of evidence indicate that Wnt/β-catenin signaling plays a fundamental role in colorectal cancer (CRC) initiation and progression. Recent genome-wide data have confirmed that in CRC this pathway is one of the most frequently modified by genetic or epigenetic alterations affecting almost 90% of Wnt/β-catenin gene members. A major challenge is thus learning how the corrupted coordination of this pathway is tied to other signalings to enhance cell growth. Peroxisome proliferator activated receptor γ (PPARγ) is emerging as a growth-limiting and differentiation-promoting factor. In tumorigenesis it exerts a tumor suppressor role and is potentially linked with the Wnt/β-catenin pathway. Based on these results, the identification of new selective PPARγ modulators with inhibitory effects on the Wnt/β-catenin pathway is becoming an interesting perspective. Should, in fact, these molecules display such properties, new research avenues would be opened aimed at developing new molecular targeted drugs. Herein, we review the basic principles and present new hypotheses underlying the crosstalk between Wnt/β-catenin and PPARγ signaling. Furthermore, we discuss the advances in our understanding as to how their altered regulation can culminate in colon cancer and the efforts aimed at designing novel PPARγ agonists endowed with Wnt/β-catenin inhibitory effects to be used as therapeutic and/or preventive agents.
Multiple lines of evidence indicate that Wnt/β-catenin signaling plays a fundamental role in colorectal cancer(CRC)initiation and progression.Recent genome-wide data have confirmed that in CRC this pathway is one of the most frequently modified by genetic or epigenetic alterations affecting almost 90%of Wnt/β-catenin gene members.A major challenge is thus learning how the corrupted coordination of this pathway is tied to other signalings to enhance cell growth.Peroxisome proliferator activated receptorγ(PPARγ)is emerging as a growth-limiting and differentiation-promoting factor.In tumorigenesis it exerts a tumor suppressor role and is potentially linked with the Wnt/β-catenin pathway.Based on these results,the identification of new selective PPARγmodulators with inhibitory effects on the Wnt/β-catenin pathway is becoming an interesting perspective.Should,in fact,these molecules display such properties,new research avenues would be opened aimed at developing new molecular targeted drugs.Herein,we review the basic principles and present new hypotheses underlying the crosstalk between Wnt/β-catenin and PPARγsignaling.Furthermore,we discuss the advances in our understanding as to how their altered regulation can culminate in colon cancer and the efforts aimed at designing novel PPARγagonists endowed with Wnt/β-catenin inhibitory effects to be used as therapeutic and/or preventive agents.
基金
Supported by Ministero dell’Istruzione,Università e Ricerca,MIUR-PRIN 2010-2011,No.prot.2010W7YRLZ_003
