Oct4 suppresses IR‑induced premature senescence in breast cancer cells through STAT3- and NF‑κB-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 (γ-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) (Tyr705) and inhibitor of nuclear factor κB (NF-κB), and blockade of these pathways with siRNA against STAT3 and/or specific inhibitors of STAT3 and NF-κB significantly increased IR-induced senescence. Secretome analysis revealed that Oct4 upregulated interleukin 24 (IL-24) expression through STAT3 and NF-κB 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-κB-mediated IL-24 production.

Role of STAT3 signaling pathway in breast cancer

“…A recent study shows that Oct-4 and c-myc can form a signal circuit to increase Adriamycin resistance in breast cancer [69]. Meanwhile, Kim et al have discovered that Oct-4 confers radiation resistance via STAT3 and NF-Bmediated IL-24 production in breast cancer cells [70]. In addition, paclitaxel is widely used as a clinical drug of breast cancer treatment, and phosphorylated STAT3 could mediate Survivin to promote paclitaxel resistance [71].…”

Radiation Response of Murine Embryonic Stem Cells

“…ESCs share some characteristics with cancer stem cells such as the capability for self-renewal [ 21 , 22 ] and are therefore of high interest for cancer research. Cancer stem cells are described to have high tolerance towards DNA damage [ 5 ], robust cytoprotective pathways [ 5 ] and expression of ESCs factors such as octamer-binding transcription factor 4 (Oct4), which might confer them radioresistance [ 23 ]. In contrast, it has been previously shown that mESCs are more sensitive to irradiation with UV light or γ-rays than differentiated mouse embryonic fibroblasts (MEFs) [ 24 ], which might be explained by a more open chromatin configuration [ 24 , 25 ] and their high proliferation rate, which goes along with a short G1 phase of the cell cycle [ 5 , 26 ].…”

miRNAs as radio‐response biomarkers for breast cancer stem cells

“…In contrast, triple-negative BCSCs in all IR doses significantly increased the expression of CD44 + /CD24 À/low surface markers, which has been related to radioresistance and poor prognosis in BC patients (Kim et al, 2016;Phillips Wang et al, 2017). In the same way, pluripotency (Kim et al, 2018;Takahashi and Yamanaka, 2006) and EMT-related gene (Theys et al, 2016;Zhou et al, 2011) differences observed for each cell line after treatment can be explained by the different sensitivity of BC molecular subtypes to IR (Kim et al, 2015). For the in vivo tumorigenic capacity after IR, the MDA-MB-231 TNBC cell line was chosen because of its described increased stemness properties, the potent migratory response, and aggressiveness in mice (Price et al, 1999).…”

“…In contrast, triple‐negative BCSCs in all IR doses significantly increased the expression of CD44 + /CD24 −/low surface markers, which has been related to radioresistance and poor prognosis in BC patients (Kim et al , ; Phillips et al , ; Wang et al , ). In the same way, pluripotency (Kim et al , ; Takahashi and Yamanaka, ) and EMT‐related gene (Theys et al , ; Zhou et al , ) differences observed for each cell line after treatment can be explained by the different sensitivity of BC molecular subtypes to IR (Kim et al , ).…”