microRNA-21-5p from M2 macrophage-derived extracellular vesicles promotes the differentiation and activity of pancreatic cancer stem cells by mediating KLF3

Abstract

Aim Given the fact that tumor-associated macrophage-derived extracellular vesicles (EVs) are attributable to tumor aggressiveness, this research intends to decode the mechanism of M2 macrophage-derived EVs in the differentiation and activities of pancreatic cancer (PaCa) stem cells via delivering microRNA (miR)-21-5p. Methods Polarized M2 macrophages were induced, from which EVs were collected and identified. miR-21-5p expression in M2 macrophage-derived EVs was tested. After cell sorting, CD24+CD44+EpCAM+ stem cells were co-cultured with M2 macrophages, in which miR-21-5p was upregulated or downregulated. The effects of M2 macrophage-derived EVs and miR-21-5p on Nanog/octamer-binding transcription factor 4 (Oct4) expression, sphere formation, colony formation, invasion and migration capacities, apoptosis, and in vivo tumorigenic ability were examined. Krüppel-like factor 3 (KLF3) expression and its interaction with miR-21-5p were determined. Results M2 macrophage-derived EVs promoted PaCa stem cell differentiation and activities. miR-21a-5p was upregulated in M2 macrophage-derived EVs. miR-21a-5p downregulation in M2 macrophage-derived EVs inhibited Nanog/Oct4 expression and impaired sphere-forming, colony-forming, invasion, migration, and anti-apoptosis abilities of PaCa stem cells in vitro and tumorigenic ability in vivo. miR-21-5p targeted KLF3 to mediate the differentiation and activities of PaCa stem cells, and KLF3 was downregulated in PaCa stem cells. Conclusion This work explains that M2 macrophage-derived exosomal miR-21a-5p stimulates differentiation and activity of PaCa stem cells via targeting KLF3, paving a novel way for attenuating PaCa stemness. Graphical abstract

Tumor-Derived Extracellular Vesicles: A Means of Co-opting Macrophage Polarization in the Tumor Microenvironment

“…While not discussed in this review, it is important to note that macrophages also secrete EVs within the TME that are able to drive or inhibit tumor progression (Goughnour et al, 2020;Zhang et al, 2020;Chang et al, 2021;Liu et al, 2021;Xavier et al, 2021). This cross-talk between tumors and macrophages, can result in complex paracrine and autocrine circuits that affect disease progression.…”

Small extracellular vesicle non-coding RNAs in pancreatic cancer: molecular mechanisms and clinical implications

“…Mechanistically, effects were attributed to miRNA-501-3p inhibiting TGFBR3, thereby inducing the TGF-β signaling pathway [82]. In addition to the aforementioned ncRNAs, TAM sEVs were also shown to overexpress well-known oncogenic miRNA-21 [83]. Horizontal transfer to PDAC cells downregulates KLF3, which promoted the stemness of PDAC cells as assessed by expression levels of Nanog and Oct4, tumorsphere, and colony formation assay [83].…”

Role of non-coding RNAs in tumor progression and metastasis in pancreatic cancer

“…Similarly, ex-miRNAs can be secreted from CAFs, TAMs, and other cell types in the TME to affect a variety of cellular processes in the recipient cancer cells (Fig. 5, [61,[118][119][120][121][122][123][124][125]). Ex-miR-222 secreted from more aggressive and metastasis-prone cancer cells can stimulate proliferative and invasion program in neighboring cancer cells by downregulating the expression and activity of cyclin-dependent kinase inhibitor p27 [114].…”

“…In cancer cells, miR-501-3p downregulates expression of TGFβR3, whose shedded ectodomain curtails TGF-β signaling, to favor migration and invasive behavior [122]. In cancer cells, miR-21 downregulates the expression of transcription factor KLF3 to promote NANOG/OCT4-dependent cancer cell stemness program [123]. Pancreatic stellate cells secrete Ex-miR-21 which in recipient cancer cells activates PI3K/ AKT pathway and promotes EMT program and MMP2/9mediated ECM remodeling [124].…”