miR clusters target cellular functional complexes by defining their degree of regulatory freedom

Abstract

Using the two paralog miR-23∼27∼24 clusters as an example and combining experimental and clinical data in a systematical approach to microRNA (miR) function and dysregulation, a complex picture of their roles in cancer is drawn. Various findings appear to be contradictory to a larger extent and cannot be fully explained by the classical regulatory network models and feedback loops that are mainly considered by one-to-one regulatory interactions of the involved molecules. Here, we propose an extended model of the regulatory role of miRs that, at least, supplements the usually considered single/oligo-target regulation of certain miRs. The cellular availability of the participating miR members in this model reflects an upper hierarchy level of intracellular and extracellular environmental influences, such as neighboring cells, soluble factors, hypoxia, chemotherapeutic drugs, and irradiation, among others. The novel model is based on the understanding of cellular functional complexes, such as for apoptosis, migration, and proliferation. These complexes consist of many regulatory components that can be targeted by miR cluster members to a different extent but may affect the functional complex in different ways. We propose that the final miR-related effect is a result of the possible degree of regulatory freedom provided by the miR effects on the whole functional complex structure. This degree of regulatory freedom defines to which extent the cellular functional complex can react in response to regulatory triggers, also understood as sensitization (more regulatory response options) or de-sensitization (less regulatory response options) of the system rather than single molecules.

Dysregulation of miRNA Expression in Cancer Associated Fibroblasts (CAFs) and Its Consequences on the Tumor Microenvironment

“…These different observations of dysregulated miR has also been observed in other context for which the authors provided the model of regulators freedom for miR regulation (see review in ref. [8]).…”

“…They have to be differentiated from miR families where sequence homology is the major determinant. Clustering appears to be an important way of evolutionary spreading of miR genes throughout the human genome and many clusters have a significant degree of evolutionary conservation [7], indicating that miR clustering is important for their biological role due to combined regulation of their expression [8]. …”

Regulation of TGF-β-mediated endothelial-mesenchymal transition by microRNA-27

“…Members of miR-23/24/27 have been proposed to have important roles in angiogenesis (5–8). In addition, deregulated expression of these miRNAs and cancer-related roles have been described in many studies with varying results (9). miR-23 and miR-27 are shown to facilitate EMT in several types of cancer including lung cancer (9).…”

“…In addition, deregulated expression of these miRNAs and cancer-related roles have been described in many studies with varying results (9). miR-23 and miR-27 are shown to facilitate EMT in several types of cancer including lung cancer (9). We also previously reported that TGF-β induces the expression of miR-23a in A549 lung cancer cells (10).…”

MicroRNAs in the Communication between Cancer Associated Fibroblasts (CAF) and Cancer Cells

“…Clustering appears to be an important way of evolutionary spreading of miR genes throughout the human genome and many clusters have a significant degree of evolutionary conservation [7], indicating that miR clustering is important for their biological role due to combined regulation of their expression. [8] The aim of this review was to summarize the current understanding on a) how miRs are involved in cancer cell -tumor environment/stroma communication, specifically the transformation of NFs into CAFs, their involved targets and signaling pathways in these interactions; and b) whether CAFrelated miR expression profiles are clinically relevant. By reviewing the literature we also found evidence that miRs have very similar roles in the activation of hepatic (HSC) and pancreatic stellate cells (PSC) which are also specifically activated fibroblasts being part of precancerous fibrotic diseases, like pancreatic and hepatic fibrosis.…”