Our group has recently reported that about 33.8% of tumor tissues in Taiwan Colorectal cancer (CRC) patients contains an APC mutation, which is close to the other reports in Asia, but significantly lower than that in western countries (70-80%). This may indicate the different mechanism and clinical treatment of colorectal carcinogenesis existed in Asia and western countries. As we know, β-catenin is shown to be a major oncoprotein in CRC development. Its oncogenic function as a transcriptional activator is upregulated by loss function in the APC tumor suppressor gene, leading to a constitutive activation of the proliferation-associated genes c-myc, cyclin D and MMP-1. Previous report showed that overexpression of MMP-1 in the collagen microenvironment increases ERK1/2 phosphorylation and high-mobility group A2 (HMGA2) expression, and contributes to gemcitabine resistance. Our group found that patients with APC mutation/high miR-21 expression had lower APC gene expression and poorer overall survival rates. In addition, we also found that HMGA2 may potentially serve as a biomarker for predicting aggressive CRC with poor survivability and as an indicator of better response to radiotherapy. This suggests that loss function of APC gene may associated with chemotherapy resistance by HMGA2 activation through β-catenin/MMP-1 pathway. Therefore, we will verify whether HMGA2 could be used as biomarker in tumor recurrence and therapeutic response of CRC with different APC status. First year: To understand whether the expression levels of miR-21, HMGA2, APC, and β-catenin associated genes in circulating tumor cells, blood and tissues of CRC patients with different APC status are correlated with clinical parameters, clinical outcomes and the response of chemotherapy or radiotherapy. In this year, we want to know whether these changes could be used as biomarkers for diagnosis and therapeutic response. Second year: To understand the underling molecular mechanism of HMGA2-mediated metastasis and drug resistant in CRC cell lines with different APC status. In this year, we want to know whether MMP-1-mediated HMGA2 could have different mechanisms to result in drug resistance of APC- wild type and –mutated cells. The primary culture CRC cell lines will be established in this year. Third year: Animal models will be used in this year to know the role of MMP-1/ β-catenin/ HMGA2 signaling in tumor metastasis and therapeutic response of CRC. The underling molecular mechanism will be performed in human tissues, cell and animal model and which signaling pathway could be involved in up-regulation of HMGA2 will be elucidated. The results obtained from this project may be found out markers to predict therapeutic response in resected CRC patients with different APC status and offering a possible strategy to overcome the drug resistance and consequently to improve outcome in CRC.
|Effective start/end date||8/1/14 → 7/31/15|