IL6-Mediated Suppression of miR-200c Directs Constitutive Activation of Inflammatory Signaling Circuit Driving Transformation and Tumorigenesis

Abstract

SUMMARY Abnormal inflammatory signaling activation occurs commonly in cancer cells. However, how it is initiated and maintained, and its roles in early stages of tumorigensis are largely unknown. Here we report that the monocyte-derived MCP-1-induced transformation of immortal breast epithelial cells is triggered by transient activation of MEK/ERK and IKK/NF-κB pathways, and maintained by constitutive activation of a feed-forward inflammatory signaling circuit composed of miR-200c, p65, JNK2, HSF1 and IL6. Suppression of miR-200c by IL6 constitutively activates p65/RelA and JNK2, and the latter phosphorylates and activates HSF1. In turn, HSF1 triggers demethylation of the IL6 promoter that facilitates the binding of p65 and c-Jun that together drives constitutive IL6 transcription. Importantly, this signaling circuit is manifest in human cancer cells and in a mouse model of ErbB2-driven breast cancer, where IL6 loss significantly impairs tumorigenesis. Therefore, targeting this signaling circuit represents an effective therapeutic avenue for breast cancer prevention and treatment.

An integrated transcriptional regulatory circuit that reinforces the breast cancer stem cell state

“…Given the central role of the Zeb repressors in controlling miRNA expression, it is tempting to speculate that they are major targets of IL6 action. In this regard, after this work was completed, it has been reported that IL6 suppresses miR-200c expression to drive activation of inflammatory signaling and tumorigenesis (32).…”

How to Explain the Contradiction of microRNA 200c Expression and Survival in Solid Tumors?: a Meta-analysis

“…Matjaz Rokavec reported that the supression of miRNA 200c by IL6 activated a feedforward inflammatory signaling circuit which drives transformation and tumorigenesis of normal cells and loss of IL6 and conservation of miRNA 200c impairs tumorigenesis significantly (Rokavec et al, 2012).…”

“…It is documented that the suppression of miRNA200c by interleukin 6 (IL6) drives transformation and tumorigenesis (Rokavec et al, 2012). Increasing evidence also demonstrate that miRNA 200c plays an critical role in epithelial-mesenchymal transition (EMT) which enhance the migration and invasion of tumor cells and eventually lead to metastasis (Mongroo et al, 2010;Dykxhoorn 2010).…”

Correlation of Levels of IL-6 with Tumor Burden and Receptor Status in Patients of Locally Advanced Carcinoma Breast

“…Various studies have shown that the disease usually takes aggressive course where the IL-6 level is found to be elevated thereby indicating possibility of it being used as prognostic marker [9]. It is accepted that IL-6 promotes tumoral growth by upregulating antiapoptotic and angiogenic proteins in tumor cells [4][5][6]. Levels of IL-6 are reported to be considerably high in cancer patients compared to healthy control subjects [7,8].…”

“…Interleukin-6 (IL-6) is mainly secreted by fibroblasts, macrophages and lymphocytes (mainly TH2 cells). It promotes tumor growth by up-regulating antiapoptotic and angiogenic proteins in tumor cells [4][5][6]. Serum interleukin-6 values have been shown to be significantly more in patients with breast cancer as compared to normal healthy women, which was correlated with clinical stage of disease and poor survival [7][8][9].…”