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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Research Article Oncology

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 4

The transcriptional function of Nanog is required for it to induce a stem-like phenotype and activate an antiapoptotic program in human cancer cells.

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The transcriptional function of Nanog is required for it to induce a ste...
(A and B) Western blot analysis of (A) Nanog, pAkt, or Akt as well as (B) cyclin A or p21 expression in P0 cells transfected with either Nanog WT or Nanog MT cDNA. (C) Growth rate of Nanog WT– transfected cells versus that of Nanog MT–transfected cells in culture. (D) Sphere-forming capacity of Nanog WT–transfected P0 cells versus that of Nanog MT–transfected P0 cells in low-density suspension culture. Original magnification, ×40. (E) Flow cytometry analysis of the frequency of apoptotic (active caspase-3+) cells in Nanog WT– or Nanog MT–transfected P0 cells after incubation with E7-specific CTLs. (F) Western blot analysis of expression of a panel of proapoptotic or antiapoptotic proteins in Nanog WT– or Nanog MT–transfected P0 cells. (G) Western blot analysis of Mcl-1 expression in Nanog-transfected P0 cells treated with siGFP or siRNA-targeting Mcl-1 (siMcl-1). Flow cytometry analysis of the frequency of apoptotic (active caspase-3+) cells in Nanog-transfected P0 cells treated with siGFP or siMcl-1 after incubation with E7-specific CTLs. (H and I) Western blot analysis of Nanog-transfected P0 cells, characterizing expression of pAkt, Akt, p21, and Mcl-1 after delivery of either (H) API2 and DMSO control or (I) Akt-specific siRNA and siGFP control. β-Actin was included as an internal loading control (A, B, and F–I). (A, B, and F–I) Numbers below blots indicate expression as measured by fold change. Error bars represent mean ± SD.