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研究摘要：
The treatment strategies of metastatic colorectal cancer (mCRC) largely correlate with drug resistance mechanisms, Subproject 1 and 2 have established 5-FU- and oxaliplatin-resistant CRC cell lines. The roles of some mediators (including metabolism, EMT, tumor microenvironment, and DNA repair) in resistant CRC cells will be further investigated in the all Subprojects. In addition, Subproject 1 investigated the composition of plasma membrane proteome, phosphoproteome, and kinome of resistant CRC cells, which will provide the proof of concept of molecules involved in tumor microenvironment (Subproject 3) and metastasis (Subproject 4). In Subproject 3, how does surrounding stromal cells of CRC respond to resistant cells-derived cytokines, leading to other cytokines release will be investigated. The very recent study indicated metastasis can occur early in human colorectal cancer before diagnosis and highlights the critical need to identify specific molecules in metastasis. Thus, in Subproject 4, the functional role and molecular mechanism of strong mediators of metastatic-TM4SF1/DDR1 in metastasis and resistant CRC cells will be investigated. DNA repair potential has to be taken into account attempting to chemotherapy and a high activity of DNA repair genes was hypothesized as a predisposition to metastasis. Therefore, Subproject 5 investigated the function of ubiquitin-conjugating enzyme E2 S (UBE2S) on DNA repair in resistance CRC cells and evaluate the inhibition effects of SMD-B1 in drug resistant CRC cells and zebrafish tumor xenograft model. Zebrafish have been shown as a metastasis model of cancer cells and the visible zebrafish embryo has the advantage of being able to analyze the metastasis of human tumor cells with fluorescent labeling. Therefore, zebrafish tumor xenograft model of Subproject 5 will also provide the platform to study the functional roles of potential mediators from all the subprojects in vivo.
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