The inflammatory/cancer-related IL-6/STAT3/NF-κB positive feedback loop includes AUF1 and maintains the active state of breast myofibroblasts

Abstract

The IL-6/STAT3/NF-κB positive feedback loop links inflammation to cancer and maintains cells at a transformed state. Similarly, cancer-associated myofibroblats 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 fibroblasts 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 myofibrobalsts to a normalized state, suggesting the implication of the IL-6 autocrine feedback loop as well. Importantly, the IL-6/STAT3/NF-κB pro-inflammatory circuit was also active in cancer-associated fibroblasts isolated from breast cancer patients. Transient inhibition of STAT3 by specific siRNA in active fibroblasts 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 myofibroblasts with caffeine, which has been previously shown to persistently inhibit active breast stromal fibroblasts, 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 fibroblasts. We have also shown that normalizing myofibroblasts, which could be of great therapeutic value, is possible through the inhibition of this procarcinogenic circuit.

AUF1 regulation of coding and noncoding RNA

“…For example, AUF1 binding is associated with stabilization of some transcripts. In a breast fibroblast cell model, SDF‐1 , α‐SMA , TGF‐β1 , and IL‐6 mRNAs were collectively stabilized by AUF1 as part of an IL‐6/STAT3/NF‐κB‐driven proinflammatory positive feedback loop . Similarly, AUF1 silencing suppressed expression of a cohort of AUF1‐targeted mRNAs identified by PAR‐CLIP.…”

TXNDC5 synergizes with HSC70 to exacerbate the inflammatory phenotype of synovial fibroblasts in rheumatoid arthritis through NF-κB signaling

“…The NF-κB signaling pathway is important for RA inflammation and can be activated by various pro-inflammatory factors such as IL-6 and TNF-α. 16,17 To further confirm the regulation of TXNDC5 by NF-κB signaling, we studied the effects of an NF-κB inhibitor on IL-6-or TNF-α-induced TXNDC5 expression. As expected, inhibition of NF-κB signaling could also attenuate the induction of TXNDC5 in response to IL-6 (Figure 2e, II) or TNF-α (Figure 2e, III).…”

RNA-Binding Proteins as Important Regulators of Long Non-Coding RNAs in Cancer

“…There is no evidence so far that AUF1 is associated with one of these two complexes, but it is generally believed to facilitate the assembly of other deadenylase complexes [91,92]. The post-transcriptional regulation of mRNA by AUF1 is more complex however, and AUF1 binding does not only induce RNA degradation but can also have quite the contrary effect, namely stabilizing mRNA or promoting translation [93,94]. Accordingly, also the implications of AUF1 in cancer are diverse and it has been found to exert both tumorigenic as well as tumor-suppressive effects [92,[95][96][97].…”