Recently, a molecular pathway linking inflammation to cell transformation has been discovered. deterministic model, we show that an irreversible bistable switch between a transformed and a non-transformed state of the cell is at the core of the dynamical behavior of the positive feedback loop linking inflammation to cell transformation. The model indicates that inhibitors (tumor suppressors) or activators (oncogenes) of this positive feedback loop regulate the occurrence of the epigenetic switch by modulating the threshold of inflammatory signal (Src) needed to promote cell Rabbit Polyclonal to TRXR2 transformation. Both stochastic simulations and deterministic simulations of a heterogeneous cell population suggest that random fluctuations (due to molecular noise or cell-to-cell variability) are able to trigger cell transformation. Moreover, the model predicts that oncogenes/tumor suppressors respectively decrease/increase the robustness of the non-transformed state of the cell towards random fluctuations. Finally, the model accounts for the potential effect of competing endogenous RNAs, ceRNAs, on the dynamics of the epigenetic switch. Depending on 202983-32-2 their microRNA targets, the model predicts that ceRNAs could act as oncogenes or tumor suppressors by regulating the occurrence of cell transformation. Author Summary An increasing amount of evidence demonstrates a close relation between inflammation and cancer development, which reveals the importance of the tumor microenvironment for the development of cancers. Recently, a molecular pathway linking inflammation to cell transformation, which is a prerequisite to cancer development, has been discovered. This molecular pathway is based on a positive inflammatory feedback loop between NF-B, Lin28, Let-7 microRNA and IL6, allowing the occurrence of an epigenetic switch leading to cell transformation. Here, we propose a computational model to account for the dynamics of this epigenetic switch. We show that an irreversible bistable switch is at the core of the dynamics of the system. The model further indicates that oncogenes (activators of the switch) and tumor suppressors (inhibitors of the switch) regulate the occurrence of cell transformation by modulating the threshold of inflammatory signal needed to induce the switch. Stochastic simulations of the model suggest 202983-32-2 that molecular fluctuations are able to trigger cell transformation, highlighting possible links between stochasticity and cancer development. Finally, the model predicts a crucial role of competing endogenous RNAs (ceRNAs) for the dynamics of the epigenetic switch and the occurrence of cell transformation. Introduction The characteristics of cancer rest on many biological capabilities acquired during the multistep of the development of tumors [1]. 202983-32-2 These biological properties include sustaining proliferative signaling, evading growth suppressors, resisting cell death, allowing replicative immortality, promoting angiogenesis, and eliciting formation of metastasis [1]. The progression from normal cells to cancer could be strongly influenced by the tumor microenvironment. In that context, many studies have shown close relations between inflammation and different types of cancer [2]C[4]. Inflammatory molecules, such as the interleukin-6 (IL6) or the transcription factor NF-B, could provide growth signals, which elicit the proliferation of malignant cells [5], [6]. However, until recently, the molecular regulatory network linking inflammation to cell transformation was poorly understood. To study the molecular link between inflammation and cancer, Iliopoulos and coworkers used an experimental model of oncogenesis, which involves a derivative of MCF10A, a spontaneous immortalized cell line derived from normal mammary epithelial cells containing ER-Src, a fusion of the oncoprotein Src with the ligand binding domain of estrogen receptor [7]. They demonstrated that transient treatment with tamoxifen results in stable cell transformation, defined by their invasive capabilities, their increased motility, as well as their ability to form mammospheres (multicellular structure enriched in cancer stem cells). This stable cell transformation can be defined as an epigenetic switch, which corresponds to a stable cell change to 202983-32-2 another phenotype without any change in DNA sequence. The triggering event of the epigenetic switch is mediated by a transient inflammatory signal driven by the Src oncoprotein [7]. After the triggering event, the transformed state of the cell mediated by the epigenetic switch is stable for many generations. A positive inflammatory feedback loop driven by the transcription factor NF-B, the microRNA binding protein Lin28, the Let-7 microRNA, and IL6 is responsible for the maintenance of this transformed state.