Hypoxic Lung-Cancer-Derived Extracellular Vesicle MicroRNA-103a Increases the Oncogenic Effects of Macrophages by Targeting PTEN

Abstract

Hypoxia, the most commonly observed characteristic in cancers, is implicated in the establishment of an immunosuppressive niche. Recent studies have indicated that extracellular vesicle (EV)-mediated cancer-stroma interactions are considered to play a critical role in the regulation of various cellular biological functions, with phenotypic consequences in recipient cells. However, the mechanisms underlying the relationship between EVs and hypoxia during cancer progression remain largely unknown. In this study, we found that EVs derived from hypoxic lung cancers increased M2-type polarization by miR-103a transfer. Decreased PTEN levels caused by hypoxic cancer-cell-derived EV miR-103a increased activation of AKT and STAT3 as well as expression of several immunosuppressive and pro-angiogeneic factors. In contrast, inhibition of miR-103a by an miRNA inhibitor effectively decreased hypoxic cancer-mediated M2-type polarization, improving the cytokine prolife of tumor infiltration macrophages. Macrophages received cancer-cell-derived EV miR-103a feedback to further enhance cancer progression and tumor angiogenesis. Finally, circulating EV miR-103a levels were higher in patients with lung cancer and closely associated with the M2 polarization. In conclusion, our results delineate a novel mechanism by which lung cancer cells induce immunosuppressive and pro-tumoral macrophages through EVs and inspire further research into the clinical application of EV inhibition or PTEN restoration for immunotherapy.

Exosomal miR‐103a‐3p ameliorates lipopolysaccharide‐induced immune response in BEAS‐2B cells via NF‐κB pathway by targeting transducin β‐like 1X related protein 1

“…Previous studies have confirmed that ADAM10 was a target of miR‐103a‐3p, and silencing of ADAM10 abated the inflammation of murine abdominal aorta . Moreover, miR‐103a‐3p negatively regulates PTEN expression, leads to the increased expression of immunosuppressive factors in lung cancer cells . Jung's team proved that mutations of TBL1XR1 increased pro‐inflammatory cytokines, leading to severe multi‐organ inflammation.…”

“…34 Moreover, miR-103a-3p negatively regulates PTEN expression, leads to the increased expression of immunosuppressive factors in lung cancer cells. 35 Jung's team proved that mutations of TBL1XR1 increased pro-inflammatory cytokines, leading to severe multi-organ inflammation. In our work, we found that exosomal miR-103a-3p binds directly to a specific region of TBL1XR1, inhibiting LPS-induced immune response, which is consistent with Jung et al's finding.…”

Hsa_circ_0033155: A potential novel biomarker for non‑small cell lung cancer

“…It was also demonstrated that the level of PTEN in NSCLC cell lines was markedly decreased, and that the overexpression of hsa_circ_0033155 significantly enhanced the level of PTEN, revealing the regulatory role of hsa_circ_0033155 on PTEN expression. Emerging studies have demonstrated that circRNA functions as miRNA sponges, removing the inhibitory effect of miRNA on its target genes, and further regulating the expression of target genes, including PTEN (26,27). The miRNA that is regulated by hsa_circ_0033155, subsequently regulating the level of PTEN remains to be investigated.…”

MicroRNA—A Tumor Trojan Horse for Tumor-Associated Macrophages

“…Hsu et al investigated the relationship between EVs and hypoxia upon lung cancer progression [137]. They found that EV-encapsulated miR-103a levels were higher in patients with lung cancer and closely associated with macrophage M2 polarization.…”