Nanog signaling in cancer promotes stem-like phenotype and immune evasion
Kyung Hee Noh, … , T.-C. Wu, Tae Woo Kim
Kyung Hee Noh, … , T.-C. Wu, Tae Woo Kim
Published October 24, 2012
Citation Information: J Clin Invest. 2012;122(11):4077-4093. https://doi.org/10.1172/JCI64057.
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Nanog signaling in cancer promotes stem-like phenotype and immune evasion

Abstract

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.

Authors

Kyung Hee Noh, Bo Wook Kim, Kwon-Ho Song, Hanbyoul Cho, Young-Ho Lee, Jin Hee Kim, Joon-Yong Chung, Jae-Hoon Kim, Stephen M. Hewitt, Seung-Yong Seong, Chih-Ping Mao, T.-C. Wu, Tae Woo Kim

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Figure 6

Nanog is a transcriptional activator of Tcl1a.

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Nanog is a transcriptional activator of Tcl1a. (A and B) Quantitative RT...
(A and B) Quantitative RT-PCR analysis of Tcl1a mRNA expression (A) in P0 or P3 cells or (B) in P0 cells transfected with empty vector or Nanog cDNA. β-Actin was included as an internal loading control. (C) Diagram of plasmids encoding wild-type (WT) or mutant (Mut) Tcl1a promoter (nt –1,286 to +1) cloned into pGL3 vector containing the luciferase gene. In the mutant plasmid, the adenine residues in the Nanog-binding site (nt –796 to –791) have been replaced with cytosine residues to diminish Nanog binding (left). Luciferase enzymatic assay in P0 or P3 cells transfected with the indicated plasmids (right). Error bars represent mean ± SD. (D) Strategy for ChIP assay, in which a fragment corresponding to nt –938 to –721, which contains the Nanog-binding region, of the Tcl1a promoter is amplified by PCR (left). Representative gel of ChIP assay in P0 and P3 cells. Input was included as positive control, and IgG was included as negative control (right). Numbers below blots indicate expression as measured by fold change.