Argonaute 2 promotes myeloma angiogenesis via microRNA dysregulation

Abstract

BackgroundDysregulated microRNA (miRNA) expression contributes to cancer cell proliferation, apoptosis and angiogenesis. Angiogenesis is a hallmark of multiple myeloma (MM) development and progression. Argonaute 2 (AGO2) protein, a core component of the RNA-induced silencing complex (RISC), can directly bind to miRNAs and mediate target messenger RNA (mRNA) degradation. A previous study showed that AGO2 knockdown suppressed human umbilical vein endothelial cell (HUVEC) growth and tube formation. However, the roles and molecular mechanisms of AGO2-induced myeloma angiogenesis are not yet fully understood. The aim of this study was to characterize these roles and effects and their associated mechanisms.ResultsSupernatants from AGO2-overexpressing MM lines induced HUVEC migration and accelerated tube formation. Conversely, supernatants from AGO2-knockdown MM lines suppressed HUVEC cell migration and tube formation. Moreover, a chick chorioallantoic membrane (CAM) assay was used to demonstrate that AGO2 could drive neovessel formation in MM lines in vivo. Using an miRNA microarray, we observed that 25 miRNAs were upregulated and 7 were downregulated in response to AGO2. Most let-7 family members and 2 miR-17/92 cluster members (miR-17a and miR-92-1), all known pro-angiogenic miRNAs, were positively regulated by AGO2 whereas anti-angiogenic miRNAs such as miR-145 and miR-361 were negatively regulated by AGO2.ConclusionsWe conclude that AGO2 can drive neovessel formation in vitro and in vivo by dysregulating the expression of some angiogenic miRNAs. The pro-angiogenic miRNAs of the let-7 family and the miR-17/92 cluster, along with the anti-angiogenic miRNA miR-145, play crucial roles in AGO2-mediated angiogenesis by targeting angiogenesis-related genes.

Total Blood Exosomes in Breast Cancer: Potential Role in Crucial Steps of Tumorigenesis

“…The observed biological effects of BCP plasma exosomes could be due to the increased miR-92a expression in these vesicles, which we have demonstrated in the current study for the first time. This assumption is supported by previous studies which have shown that the increased level of miR-92a correlates with increased angiogenesis and cell migration activity [ 25 , 26 ].…”

“…A number of previous studies have indicated that miRNAs, being one of the main functional components of exosome cargo, may play a crucial role in cell-to-cell communication and eventually regulate the biological functions of recipient cells. It is known that miR-92a and miR-25-3p are up-regulated in cell lines with enhanced EMT, cell motility, and angiogenesis [ 25 , 26 , 27 , 28 , 29 , 30 ]. Since the miR-16-5p expression was stable and reproducible, it was chosen as an endogenous control to normalize the miRNA expression [ 30 , 31 , 32 ].…”

Circulating miRNAs in cancer: from detection to therapy

“…For example, Vickers et al reported that the uptake of miRNA high-density lipoprotein (HDL) in plasma by recipient cells appears to be dependent on a cell-surface HDL receptor named scavenger receptor class B, type I (SRBI) [ 68 ], suggesting a novel possible mechanism for the function of circulating miRNAs on the progression of atherosclerosis or cancer. Currently, several miRNA-binding proteins have been reported to participate in circulating miRNA inter-or extra-cellular communication, such as nucleophosmin1 (NPM1) [ 69 ] and Argonaute2 (Ago2) -1,-2 -3 and -4 [ 16 , 70 – 72 ].…”

Role of cereblon in angiogenesis and in mediating the antiangiogenic activity of immunomodulatory drugs

“…Notably, lenalidomide treatment of siCRBN-mediated knockdown cells showed less inhibition in tubule formation (as compared to lenalidomide-treated wild-type cells) following treatment for 18 hours ( Figure 3B). The positive control, CPS49, a well-characterized potent antiangiogenic analog of thalidomide [25][26][27][28] also inhibited lattice formation regardless of CRBN knockdown.…”