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Nanog signaling in cancer promotes stem-like phenotype and immune evasion.
Noh, Kyung Hee,Kim, Bo Wook,Song, Kwon-Ho,Cho, Hanbyoul,Lee, Young-Ho,Kim, Jin Hee,Chung, Joon-Yong,Kim, Jae-Hoon,Hewitt, Stephen M,Seong, Seung-Yong,Mao, Chih-Ping,Wu, T-C,Kim, Tae Woo American Society for Clinical Investigation 2012 The Journal of clinical investigation Vol.122 No.11
<P>Adaptation of tumor cells to the host is a major cause of cancer progression, failure of therapy, and ultimately death. Immune selection drives this adaptation in human cancer by enriching tumor cells with a cancer stem cell-like (CSC-like) phenotype that makes them resistant to CTL-mediated apoptosis; however, the mechanisms that mediate CSC maintenance and proliferation are largely unknown. Here, we report that CTL-mediated immune selection drives the evolution of tumor cells toward a CSC-like phenotype and that the CSC-like phenotype arises through the Akt signaling pathway via transcriptional induction of Tcl1a by Nanog. Furthermore, we found that hyperactivation of the Nanog/Tcl1a/Akt signaling axis was conserved across multiple types of human cancer. Inhibition of Nanog in a murine model of colon cancer rendered tumor cells susceptible to immune-mediated clearance and led to successful, long-term control of the disease. Our findings establish a firm link among immune selection, disease progression, and the development of a stem-like tumor phenotype in human cancer and implicate the Nanog/Tcl1a/Akt pathway as a central molecular target in this process.</P>