Immune selection drives the evolution of tumor cells toward an immune-resistant and cancer stem cell (CSC)-like phenotype. We reported that apoptosis inhibitor-5 (API5) acts as an immune escape factor, which has a significant role in controlling immune resistance to antigen-specific T cells, but its functional association with CSC-like properties remains largely unknown. In this study, we demonstrated for the first time that API5 confers CSC-like properties, including NANOG expression, the frequency of CD44-positive cells and sphere-forming capacity. Critically, these CSC-like properties mediated by API5 are dependent on FGFR1 signaling, which is triggered by E2F1-dependent FGF2 expression. Furthermore, we uncovered the FGF2-NANOG molecular axis as a downstream component of API5 signaling that is conserved in cervical cancer patients. Finally, we found that the blockade of FGFR signaling is an effective strategy to control API5high human cancer. Thus, our findings reveal a crucial role of API5 in linking immune resistance and CSC-like properties, and provide the rationale for its therapeutic application for the treatment of API5+ refractory tumors.
Bibliographical noteFunding Information:
Tissue microarrays containing four 1.0 mm cores from 479 formalin-fixed, paraffin-embedded cervical neoplasia tissue specimens and matched nonadjacent normal cervical epithelial tissue specimens, have been previously described. Tissue specimens were prospectively collected from patients who were admitted to Gangnam Severance Hospital between 1996 and 2010. Some of the paraffin blocks were provided by the Korea Gynecologic Cancer Bank through the Bio & Medical Technology Development Program of the Ministry of Education, Science and Technology, Korea (NRF-2012M3A9B8021800). Tissue samples were collected from patients who provided informed consent. This study was approved by the Institutional Review Board of Gangnam Severance Hospital (Seoul, South Korea) and it was additionally approved by the Office of Human Subjects Research at the National Institutes of Health.
This work was funded by the National Research Foundation of Korea (NRF-2014R1A2A1A10054205 and NRF-2013M3A9D3045881).
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cancer Research