The miRNA-21-5p Payload in Exosomes from M2 Macrophages Drives Tumor Cell Aggression via PTEN/Akt Signaling in Renal Cell Carcinoma

Abstract

M2 macrophages in the tumor microenvironment are important drivers of cancer metastasis. Exosomes play a critical role in the crosstalk between different cells by delivering microRNAs or other cargos. Whether exosomes derived from pro-tumorigenic M2 macrophages (M2-Exos) could modulate the metastatic behavior of renal cell carcinoma (RCC) is unclear. This study found that M2-Exos promotes migration and invasion in RCC cells. Inhibiting miR-21-5p in M2-Exos significantly reversed their pro-metastatic effects on RCC cells in vitro and in the avian embryo chorioallantoic membrane in vivo tumor model. We further found that the pro-metastatic mechanism of miR-21-5p in M2-Exos is by targeting PTEN-3′UTR to regulate PTEN/Akt signaling. Taken together, our results demonstrate that M2-Exos carries miR-21-5p promote metastatic features of RCC cells through PTEN/Akt signaling. Reversing this could serve as a novel approach to control RCC metastasis.

Role of exosomal ncRNAs released by M2 macrophages in tumor progression of gastrointestinal cancers

“…M2-Exos-miR-21-5p promoted tumor metastasis in RCC. 35 In the avian embryo chorioallantoic membrane in vivo tumor model as well as in vitro , tumor metastasis was prevented by miR-21-5p knockdown in M2-TMAs-Exos. 35 Furthermore, M2-Exos-miR-487a significantly promoted tumor proliferation and progression in vitro and in vivo in GC.…”

“… 35 In the avian embryo chorioallantoic membrane in vivo tumor model as well as in vitro , tumor metastasis was prevented by miR-21-5p knockdown in M2-TMAs-Exos. 35 Furthermore, M2-Exos-miR-487a significantly promoted tumor proliferation and progression in vitro and in vivo in GC. 51 Adding to that, Exos-miR-365 secreted by M2-TMAs was reported as a significant promoter of PDAC progression by downregulating the expression of BTG2, leading to the promotion of FAK/AKT signaling.…”

“…The silencing of miR-21-5p in M2-Exos significantly abolished the pro-metastatic effects of these M2-Exos in renal cell carcinoma (RCC). 35 A recent study has shown that inhibiting lncRNA-CRNDE in M2-Exos enhances sensitivity to cisplatin (CDDP) in GC. 36 Another study showed that the knock-down of miR-223 M2-Exos reduced resistance to doxorubicin in GC.…”

The Role of miRNA in the Management of Localized and Advanced Renal Masses, a Narrative Review of the Literature

“…A similar protocol was presented by He et al in a study investigating the role of exosomal miR-31-5p in the induction of resistance to sorafenib [12]. Assessment of the exosomal miRNA of the RCC microenvironment was recently shown to be relevant, as pro-tumorigenic miRNAs were found in exosomes related to the cross-talk between cancer cells and polarized M2 macrophages [13][14][15]. miRNAs directly secreted into the plasma by RCC tumor or stromal cells have also been proven to be stable in humans and were reliably isolated via RT-qPCR of a centrifuged miRNA phase [16][17][18].…”

M2 macrophage-derived exosomal miR-145-5p protects against the hypoxia/reoxygenation-induced pyroptosis of cardiomyocytes by inhibiting TLR4 expression

“…Yang et al reported ( 20 ) that exosomal miR-487a derived from M2 macrophages promotes gastric cancer progression by regulating T-cell intracellular antigen 1 (TIA1). Zhang et al found ( 21 ) that exosomes derived from M2 macrophages carrying miR-21-5p promote renal cell carcinoma (RCC) cell invasion by the activation of the Phosphatase and TENsin homolog (PTEN)/protein kinase B (Akt) RCC cell signaling pathway. Long et al suggested ( 22 ) that M2 exosomes carrying miR-1271-5p attenuate apoptosis in cardiomyocytes and promote cardiac repair by downregulating SRY-box containing gene 6 (SOX6) expression.…”