Oct4 suppresses IR-induced premature senescence in breast cancer cells through STAT3-and NF-B-mediated IL-24 production

Abstract

Breast cancer stem cells (BCSCs) are a small subpopulation of breast cancer cells that have been proposed to be a primary cause of failure of therapies, including ionizing radiation (IR). Their embryonic stem-like signature is associated with poor clinical outcome. In the present study, the function of octamer-binding transcription factor 4 (Oct4), an embryonic stem cell factor, in the resistance of BCSCs to IR was investigated. Mammosphere cells exhibited increased expression of stemness-associated genes, including Oct4 and sex-determining region Y-box 2 (Sox2), and were more resistant to IR compared with serum-cultured monolayer cells. IR-resistant MCF7 cells also exhibited significantly increased expression of Oct4. To investigate the possible involvement of Oct4 in IR resistance of breast cancer cells, cells were transfected with Oct4. Ectopic expression of Oct4 increased the clonogenic survival of MCF7 cells following IR, which was reversed by treatment with small interfering RNA (siRNA) targeting Oct4. Oct4 expression decreased phosphorylated histone H2AX (-H2AX) focus formation and suppressed IR-induced premature senescence in these cells. Mammosphere, IR-resistant and Oct4-overexpressing MCF7 cells exhibited enhanced phosphorylation of signal transducer and activation of transcription 3 (STAT3) (Tyr(705)) and inhibitor of nuclear factor B (NF-B), and blockade of these pathways with siRNA against STAT3 and/or specific inhibitors of STAT3 and NF-B significantly increased IR-induced senescence. Secretome analysis revealed that Oct4 upregulated interleukin 24 (IL-24) expression through STAT3 and NF-B signaling, and siRNA against IL-24 increased IR-induced senescence, whereas recombinant human IL-24 suppressed it. The results of the present study indicated that Oct4 confers IR resistance on breast cancer cells by suppressing IR-induced premature senescence through STAT3- and NF-B-mediated IL-24 production.