The in ammatory/cancer-related IL-6/STAT3/NF-κB positive feedback loop includes AUF1 and maintains the active state of breast myo broblasts
Aboussekhra, Siti-Fauziah Hendrayani, Bothaina Al-Harbi, Mysoon M. Al-Ansari, Gabriela Silva, Abdelilah . 2016
The IL-6/STAT3/NF-κB positive feedback loop links in ammation to cancer and maintains cells at a transformed state. Similarly, cancer-associated myo broblats remains active even in absence of cancer cells. However, the molecular basis of this sustained active state remains elusive. We have shown here that breast cancer cells and IL-6 persistently activate breast stromal broblasts through the stimulation of the positive IL-6/STAT3/NF-κB feedback loop. Transient neutralization of IL-6 in culture inhibited this signaling circuit and reverted myo brobalsts to a normalized state, suggesting the implication of the IL-6 autocrine feedback loop as well. Importantly, the IL-6/STAT3/NF-κB pro-in ammatory circuit was also active in cancer-associated broblasts isolated from breast cancer patients. Transient inhibition of STAT3 by speci c siRNA in active broblasts persistently reduced the level of the RNA binding protein AUF1, blocked the loop and normalized these cells. Moreover, we present clear evidence that AUF1 is also part of this positive feedback loop. Interestingly, treatment of breast myo broblasts with caffeine, which has been previously shown to persistently inhibit active breast stromal broblasts, blocked the positive feedback loop through potent and sustained inhibition of STAT3, AKT, lin28B and AUF1. These results indicate that the IL-6/STAT3/NF-κB positive feedback loop includes AUF1 and is responsible for the sustained active status of cancer-associated broblasts. We have also shown that normalizing myo broblasts, which could be of great therapeutic value, is possible through the inhibition of this procarcinogenic circuit.The IL-6/STAT3/NF-κB positive feedback loop links in ammation to cancer and maintains cells at a transformed state. Similarly, cancer-associated myo broblats remains active even in absence of cancer cells. However, the molecular basis of this sustained active state remains elusive. We have shown here that breast cancer cells and IL-6 persistently activate breast stromal broblasts through the stimulation of the positive IL-6/STAT3/NF-κB feedback loop. Transient neutralization of IL-6 in culture inhibited this signaling circuit and reverted myo brobalsts to a normalized state, suggesting the implication of the IL-6 autocrine feedback loop as well. Importantly, the IL-6/STAT3/NF-κB pro-in ammatory circuit was also active in cancer-associated broblasts isolated from breast cancer patients. Transient inhibition of STAT3 by speci c siRNA in active broblasts persistently reduced the level of the RNA binding protein AUF1, blocked the loop and normalized these cells. Moreover, we present clear evidence that AUF1 is also part of this positive feedback loop. Interestingly, treatment of breast myo broblasts with caffeine, which has been previously shown to persistently inhibit active breast stromal broblasts, blocked the positive feedback loop through potent and sustained inhibition of STAT3, AKT, lin28B and AUF1. These results indicate that the IL-6/STAT3/NF-κB positive feedback loop includes AUF1 and is responsible for the sustained active status of cancer-associated broblasts. We have also shown that normalizing myo broblasts, which could be of great therapeutic value, is possible through the inhibition of this procarcinogenic circuit.
