|Budget Amount *help
¥9,500,000 (Direct Cost : ¥9,500,000)
Fiscal Year 2005 : ¥2,400,000 (Direct Cost : ¥2,400,000)
Fiscal Year 2004 : ¥3,100,000 (Direct Cost : ¥3,100,000)
Fiscal Year 2003 : ¥4,000,000 (Direct Cost : ¥4,000,000)
A promising area in current cancer research explores the wide range of molecular events including aberrant/alternative gene splicing, epigenetic changes, cellular signal transduction, transcriptional regulation and post-translational modifications, which determine the fate of cells (growth, differentiation, and programmed cell death). One of such events takes place in the Wnt signaling pathway, and its aberrant activation is involved in malignant transformation of cells, β-catenin has two distinct functions, namely, maintaining cell-to-cell adhesion and mediating the Wnt/β-catenin pathway, which plays pivotal roles in embryogenesis and in certain tumors, particularly development and progression of colorectal cancer (CRC)^<16>. On the basis of our previous studies showing association of distinct patterns of β-catenin activation with malignant potential of the tumors and clinical outcome of CRC patients^6, in the present study we addressed the molecular and cellular mechanisms underlying
activation and deregulation of Wnt/β-catenin signaling in colorectal cancer.
The oncogenic properties of Wnt/β-catenin signaling stem from alteration in ubiquitin-mediated degradation and subcellular localization of β-catenin from cell membrane to the nucleus, where it binds to T cell factor (Tcf) ; the complex facilitates transcription of genes encoding factors for cell proliferation and inhibition of apoptosis. We previously found that β-transducin repeat-containing protein (β-TrCP) is a component of the ubiquitin ligase complex targeting β-catenin and IκBα for proteasomal degradation and thus a negative regulator of Wnt/β-catenin signaling and a positive regulator of NF-κB pathway. Increased induction of β-TrCP via the β-catenin/Tcf pathway results in degradation of β-catenin, indicating that a negative feedback loop controls the β-catenin/Tcf pathway under physiologic conditions (Mol Cell 2000;5:877-82). Here we demonstrated that, in CRC, increased expression of β-TrCP by an impairment in the negative feedback loop regulation between β-TrCP and β-catenin is associated with activation of both β-catenin and NF-κB, suggesting that the integration of these signaling pathways by β-TrCP overexpresion contributes to an inhibition of apoptosis and tumor metastasis^9.
As mentioned above, in non-neoplastic cells harboring wild-type CTNNB1 and APC genes, β-catenin/Tcf signaling increases levels of β-TrCP mRNA and protein in a Tcf-dependent manner (Mol Cell 2000;5:877-82). In this study, we identified a novel β-catenin/Tcf target gene X ; protein product of which binds to the coding region of β-TrCP1 mRNA and stabilizes it. It was also demonstrated that X protein is essential for induction of mRNA of β-TrCP1 as well as c-myc by β-catenin/Tcf signaling in colon cancer cells. In human CRC, increased expression of X protein and β-TrCP coincides with activation of β-catenin and NF-κB in the same tumor, which is associated, with inhibition of apoptosis and tumor metastasis (unpublished data).
With regards to the canonical view that GSK3β is a negative regulator of Wnt signaling, one may consider that it functions like a tumor suppressor in CRC. Reportedly GSK3β has opposing roles ; removing a neoplastic trigger by phosphorylation-dependent degradation of β-catenin in the ubiquitin system, and maintaining cell survival and proliferation through the NF-κB pathway. Here we demonstrated an unrecognized role (tumor supportive properties) of GSK3β in CRC by transcriptionally and pharmacologically modulating its expression and activity, and warrant proposing this kinase as a potential therapeutic target in CRC^<14>. Less