| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2001: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
It is fairly far from our expectation at the time when β-catenin was first identified as one of the key molecules in cell adhesion machinery that it is in central in the Wnt/ β-catenin/Tcf signaling pathway, which plays pivotal roles in normal embryonic development and differentiation and in malignant transformation of cells. Different mechanisms underlie oncogenic β-catenin acivation ; i.e., mutations in its phospho-acceptor sites, failure to recruit GSK3β because of APC mutation, or inhibition of GSK3β activity by Wnt-secreted proteins or PI3K/Akt signaling ; a consequence of them is abrogation of β-catenin phosphorylation. This leads stabilization of β-catenin and its translocation to the nucleus where it exerts oncogenic activities by transactivating certain effector genes including c-myc, cyclin D1, and MMP-7.
Unlike extensive characterization of K-ras that is another oncogene of great interest, many studies to clarify basic mechanisms of β-catenin's oncogenic functions have been c
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ompetitively pursued only in experimental but not clinical settings. It is only in recent years that a small number of reports on oncogenic β-catenin activation and its relevance to patients' pathology have been available for clinical colorectal cancers, showing that oncogenic β-catenin activation is an early event in colorectal cancer development. However, little is known for clinical relevance of this oncogene activation until we currently determined, in this research project, the two distinct patterns of its oncogenic nuclear accumulation (NA), represented by diffuse NA (Nad) and selective NA in the tumor invasion front only (Nainv), respectively as early and presumably late events. The presence of different activation patterns would be supported by evidence that β-catenin is activated in most colon cancers by escaping from a degradation machinery as a result of mutations in APC, which is known to be the earliest genetic alteration in colorectal tumorigenesis, and by our results that, in contrast to Nad pattern, Nainv pattern of β-catenin activation is independent to inactivation of APC. Recently we have obtained a result suggesting that β-transducing repeat-containing protein (βTrCP), a ubiquitin ligase receptor that targets β-catenin for proteasomal degradation, affects different patterns of β-catenin activation in the tumors. Our observation that is more important than the molecular mechanisms underlying the difference in activation patterns was that oncogenic β-catenin activation in the tumor invasion front is an independent and reliable indicator of membership in a subset of colon cancer patients who are highly susceptible to tumor recurrence and have a less favorable survival rate. Furthermore we have demonstrated that although activation of β-catenin and ras is independent in the process of clinical cancer development, combined analysis of the two major oncogenes can detect most colorectal cancers and identify a subset of patients with poorer outcomes.
Apparently, activation of β-catenin is a cosequence, with few exceptions, of its escaping from ubiquitin-mediated protein degradation, the process of which includes a growing numbers of regulators and effectors. More detailed information of the involvement of β-catenin in human cancers is promising for development of molecular diagnosis and treatment targeting this oncogene and regulators/effectors of its signaling. Less
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