| Summary: | 碩士 === 國立陽明大學 === 生物藥學研究所 === 103 === The signal transducers and activators of transcription (STATs) are a family of transcription factors that can regulate cell proliferation, survival, differentiation, and immune response. Numerous studies have shown that STAT3 plays a critical role in development as well as tumorigenesis. Recent work further reported that STAT3 activation is associated with enhanced malignancy and metastasis in human colorectal cancer (CRC). Moreover, several studies even demonstrated that STAT3 is not only more active in human colorectal cancer stem cells (CRSCs) but also necessary for their proliferation and survival. Accordingly, several STAT3 inhibitors have been shown to block both the viability and self-renewal ability of CRSCs. Therefore, novel agents capable of reducing the levels of active STAT3 may help in treating CRC more effectively.
Because STAT3 is activated mainly by the phosphorylation of its tyrosine 705 (Y705), a dephosphorylation of this residue leads to its inactivation. Notably, the Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1) has been identified as the major phosphatase (PPase) responsible for removing this phosphate. In this study, three novel SHP-1 activators including Sorafenib, SC-43, and SC-2001 (all kindly provided by Dr. Chung-Wai Shiau) were chosen to examine their suppressive effects on the stemness of HCT-116 and HT-29 human CRC cells. Even though all three SHP-1 activators not only inhibited sphere formation but also induced sphere shrinkage of both HCT-116 and HT-29 cells, SC-2001 was excluded in the remaining work because of its low potency. Subsequently, Sorafenib and SC-43 were shown to suppress the soft agar colony-forming abilities of HCT-116 and HT-29 cells. However, only SC-43 could decrease both the endogenous levels of active STAT3 in HCT-116 cells and the levels of IL-6-induced active STAT3 in HT-29 cells. In addition, both agents could inhibit the mRNA levels of several CRSC marker genes such as Ascl2, ALDH1, and Bmi1 and the protein levels of Bmi1, as well as reduce the CD133+/CD44+ subpopulations in both HCT-116 and HT-29 cells. Interestingly, SC-43 was found to be much more potent than Sorafenib in reducing the stemness properties in both human CRC lines which could be accounted at least in part by its higher efficacy in decreasing the levels of active STAT3 in these cells.
Collectively, these results also warrant a further investigation of whether the stemness-inhibitory effects of both Sorafenib and SC-43 in HCT-116 and HT-29 cells are solely (or mainly) due to their activation of SHP-1 which in turn diminishes the active STAT3 levels in these human CRC cells.
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