Loss of function of Adenomatous polyposis coli (APC) is an early event in the pathogenesis of colorectal cancer (CRC). In more than 80 % of CRC carry mutations and inactivate of APC resulting in accumulation of β-catenin in the nucleus, which constitutively associates with T-cell specific transcription factor (TCF) or lymphoid enhancer factor (LEF) proteins to stimulate the transcription of TCF/LEF target genes. The canonical Wnt/β-catenin pathway is activated in 90% of CRC and contributed to their growth and survival. In contrast, the noncanonical Wnt pathway do not signal through β-catenin and can antagonize the functions of canonical Wnt/β-catenin pathway. Wnt5a is the key factor of noncanonical Wnt pathway and can prevent tumor formation by association with APC in promoting the degradation of β-catenin. In Taiwan, the APC gene mutation rate (33.8%) is lower than in other countries and accompany with inactivation of APC and accumulation of β-catenin in the nucleus of CRC patients. Heat-shock protein (Hsp) 90 is a molecular chaperone and highly related to tumorigenesis. High expression of Hsp90 was found in CRC specimens to compare to normal colon controls. Hsp90 client, GSK3β, is involved in canonical Wnt/β-catenin pathway to mediate β-catenin phosphorylation into proteolytic pathway. Treatment with Hsp90 inhibitor in the cell cause downregulation of β-catenin via GSK3β-dependent manner in Hsp90 inhibition leukemia cells and eventually cell death. In our preliminary results shown that there was high expression of β-catenin mRNA in APCMut of clinical CRC tumors to compare to APCWT of clinical CRC tumors. This result may imply that overespression of Hsp90 and mutation of APC contribute this phenomenon. Since Wnt5a in promoting β-catenin degradation requires functional APC and β-catenin can be degraded by Hsp90 inhibitor via activation GSK3β-dependent manner. Thus, we hypothesize that targeting on Wnt/β-catenin pathway will provide new therapeutic opportunities for CRC patients via parallel targeting strategy with Hsp90 inhibitor treatment and reexpression of Wnt5a. Hence, this proposal is to investigate the role of Wnt5a and Hsp90 in the Wnt/β-catenin signaling pathway of CRC and following specific aims will be achieved in this proposal: Aim 1: To establish the expression correlation between Wnt5a, the component of canonical Wnt pathway and TCF/miR-21/TET signaling in CRC cell lines (Year 1~2). Aim 2: To identify the effects of novel Hsp90 inhibitor, NVP-AUY922 on canonical Wnt signaling pathway (Year 1~2). Aim 3: To detect the expression of molecules involved in canonical Wnt/β-catenin pathway as well as Hsp90-mediated signaling of clinical CRC specimens (Year 2~3). Aim 4: To investigate the in vivo anticancer effect of Hsp90 inhibitor, NVP-AUY922 on xenograft model with subcutaneously implanted HCT116 containing Wnt5a gene (Year 3).
|Effective start/end date||8/1/14 → 7/31/15|
- colorectal cancer