Amazing stuff! microRNA overlooked in the past, not anymore! Cancer is history (soon)!
"... This isn’t the first time that miRNAs were found to enhance gene expression. A paper published in Science in 2007 pointed to cases of miRNA-mediated upregulation in cells that had stopped dividing. Still, since then, upregulation was thought to be rare and limited to idle cells ...
They probed the miRNA profile of two glycosylation proteins: ST6GAL1, which is ubiquitously expressed, and ST6GAL2, which operates in just a few cell types. Work from their lab had previously found that ST6GAL1 is overactive in pancreatic cancer, peppering cancerous cells’ membranes with a sugar called 2,6-sialic acid. An abundance of sugars on their surface enables tumor cells to evade the immune system, metastasize, and invade other tissues. ...
They discovered that while the miRNAs that interact with ST6GAL2 downregulate its expression, those that interact with ST6GAL1 boost its expression and therefore increase levels of 2,6-sialic acid attachment. ...
the team soon replicated their findings in four cancer cell lines taken from the lungs, ovaries, pancreas, and colon. Furthermore, mutating potential miRNA binding sites caused the upregulation to disappear, suggesting that the miRNAs directly control the gene’s expression. ..."
They probed the miRNA profile of two glycosylation proteins: ST6GAL1, which is ubiquitously expressed, and ST6GAL2, which operates in just a few cell types. Work from their lab had previously found that ST6GAL1 is overactive in pancreatic cancer, peppering cancerous cells’ membranes with a sugar called 2,6-sialic acid. An abundance of sugars on their surface enables tumor cells to evade the immune system, metastasize, and invade other tissues. ...
They discovered that while the miRNAs that interact with ST6GAL2 downregulate its expression, those that interact with ST6GAL1 boost its expression and therefore increase levels of 2,6-sialic acid attachment. ...
the team soon replicated their findings in four cancer cell lines taken from the lungs, ovaries, pancreas, and colon. Furthermore, mutating potential miRNA binding sites caused the upregulation to disappear, suggesting that the miRNAs directly control the gene’s expression. ..."
From the abstract:
"Chemical biology has revealed the importance of sialic acids as a major signal in physiology and disease. The terminal modification α-2,6-sialic acid is controlled by the enzymes ST6GAL1 and ST6GAL2. Dysregulation of this glycan impacts immunological recognition and cancer development. microRNAs (miRNA, miR), noncoding RNAs that downregulate protein expression, are important regulators of glycosylation. Using our recently developed high-throughput fluorescence assay (miRFluR), we comprehensively mapped the miRNA regulatory landscape of α-2,6-sialyltransferases ST6GAL1 and ST6GAL2. We found, contrary to expectations, the majority of miRNAs upregulate ST6GAL1 and α-2,6-sialylation in a variety of cancer cells. In contrast, miRNAs that regulate ST6GAL2 were predominantly downregulatory. Mutational analysis identified direct binding sites in the 3′-untranslated region (UTR) responsible for upregulation, confirming it is a direct effect. The miRNA binding proteins AGO2 and FXR1 were required for upregulation. Our results upend common assumptions surrounding miRNA, arguing that upregulation by these noncoding RNA is common. Indeed, for some proteins, upregulation may be the dominant function of miRNA. Our work also suggests that upregulatory miRNAs enhance overexpression of ST6GAL1 and α-2,6-sialylation, providing another potential pathway to explain the dysregulation observed in cancer and other disease states."
High-Throughput Analysis Reveals miRNA Upregulating α-2,6-Sialic Acid through Direct miRNA–mRNA Interactions (open access)
Graphical abstract
No comments:
Post a Comment