Abstract
Cancer initiation, progression, and metastasis leverage many regulatory agents, such as signaling molecules, transcription factors, and regulatory RNA molecules. Among these, regulatory non-coding RNAs have emerged as molecules that control multiple cancer types and their pathologic properties. The human microRNA-211 (MIR211) is one such molecule, which affects several cancer types, including melanoma, glioblastoma, lung adenocarcinomas, breast, ovarian, prostate, and colorectal carcinoma. Previous studies suggested that in certain tumors MIR211 acts as a tumor suppressor while in others it behaves as an oncogenic regulator. Here we summarize the known molecular genetic mechanisms that regulate MIR211 gene expression and molecular pathways that are in turn controlled by MIR211 itself. We discuss how cellular and epigenetic contexts modulate the biological effects of MIR211, which exhibit pleiotropic effects. For example, up-regulation of MIR211 expression down-regulates Warburg effect in melanoma tumor cells associated with an inhibition of the growth of human melanoma cells in vitro, and yet these conditions robustly increase tumor growth in xenografted mice. Signaling through the DUSP6-ERK5 pathway is modulated by MIR211 in BRAFV600E driven melanoma tumors, and this function is involved in the resistance of tumor cells to the BRAF inhibitor, Vemurafenib. We discuss several alternate but testable models, involving stochastic cell-to-cell expression heterogeneity due to multiple equilibria involving feedback circuits, intracellular communication, and genetic variation at miRNA target sties, to reconcile the paradoxical effects of MIR211 on tumorigenesis. Understanding the precise role of this miRNA is crucial to understanding the genetic basis of melanoma as well as the other cancer types where this regulatory molecule has important influences. We hope this review will inspire novel directions in this field.
Highlights
MicroRNAs1 are highly conserved small non-coding RNA molecules of approximately 22 nucleotides that control gene expression either by direct translational inhibition of protein synthesis or by affecting the degradation of the target mRNA [2]. miRNA biogenesis occurs through biochemical pathways that are well conserved among metazoans [3], which is described briefly below [miRNA biogenesis has been reviewed recently [4]]
Since MIR211 has been shown to be associated with various human diseases apart from cancers, it is regarded as one of the most promising miRNA molecules for therapeutic applications
To our knowledge no clinical trial is currently on-going with this miRNA
Summary
MicroRNAs1 (miRNAs) are highly conserved small non-coding RNA molecules of approximately 22 nucleotides that control gene expression either by direct translational inhibition of protein synthesis or by affecting the degradation of the target mRNA [2]. miRNA biogenesis occurs through biochemical pathways that are well conserved among metazoans [3], which is described briefly below [miRNA biogenesis has been reviewed recently [4]]. Several MIR211 targets genes, all of which were previously known to be oncogenic, were identified, including the calcium-activated potassium channel subunit a-1 (KCNMA1) [12], Insulin-like Growth Factor 2 Receptor (IGF2R) [14], TGFbeta Receptor 2 (TGFBR2) [41], Insulin Growth Factor Binding Protein 5 (IGFBP5) [42, 43], POU domain-containing transcription factor BRN2 [25], and Nuclear Factor of Activated T-cells 5 (NFAT5) [14] These evidences together are consistent with the proposal that MIR211 exerts its tumor suppressor properties by means of direct negative regulation of potentially oncogenic mRNAs [44]. When MIR211 expression was artificially induced in human melanoma cell lines, where its expression is generally reduced relative to those in melanocytes, which were xenografted into immunodeficient mice they resulted into aggressive tumor growth [68] This surprising observation is consistent with similar oncogenic effects associated with MIR211 expression in a number of other cancer types,
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
