Downregulation of miRs 203, 887, 3619 and 182 prevent vimentin-triggered, phospholipase D (PLD)-mediated cancer cell invasion [Signal Transduction]

November 15th, 2015 by Fite, K., Gomez-Cambronero, J.

Breast cancer is a leading cause of morbidity and mortality among women. Metastasis is initiated after epithelial-mesenchymal-transition (EMT). We have found a connection between EMT markers and the expression of 4 microRNAs (miRs), mediated by the signaling enzyme phospholipase D (PLD). Low aggressive MCF-7 and BT-474 breast cancer cells have low endogenous PLD enzymatic activity and cell invasion, concomitantly with high expression of miR-203, 887 and 3619 (that decrease PLD2 translation and a luciferase reporter) and miR-182 (targeting PLD1) that are therefore tumor-suppresor like miRs. The combination miR-887+miR-3619 abolished >90% PLD enzymatic activity. Conversely, post-EMT MDA-MB-231 and BT-549 cells, have low miR expression, high levels of PLD1/2 and high aggressiveness. The latter was reversed by ectopically transfecting the miRs, which was negated by silencing miRs with specific siRNAs. We uncovered that the molecular mechanism is that E-cadherin triggers expression of the miRs in pre-EMT cells, whereas Vimentin dampens expression of the miRs in post-EMT, invasive cells. This novel work identifies for the first time a set of miRs that are activated by a major pre-EMT marker and deactivated by a post-EMT marker, boosting the transition from low invasion to high invasion, as mediated by the key phospholipid metabolism enzyme PLD.
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