Exosomes from M1‐polarized macrophages promote apoptosis in lung adenocarcinoma via the miR‐181a‐5p/ETS1/STK16 axis

Abstract

Serine/threonine kinase 16 (STK16) is crucial in on regulating tumor cell proliferation, apoptosis, and prognosis. Activated M1 macrophages regulate lung adenocarcinoma (LUAD) growth by releasing exosomes. This study aims to investigate the role of STK16 and then focus on the possible mechanisms through which exosomes derived from M1 macrophages play their roles in LUAD cells by targeting STK16. Clinical LUAD samples were used to evaluate the expression of STK16 and its association with prognosis. Exosomes were isolated from M0 and M1 macrophages by ultracentrifugation and were then identified by electron microscopy and western blotting. In vitro gain-and loss-of-function experiments with LUAD cells were performed to elucidate the functions of miR-181a-5p, ETS1, and STK16, and mouse xenograft models were used to verify the function of STK16 in vivo. Western blotting, quantitative real-time PCR, CCK-8 assay, cell apoptosis, immunohistochemistry staining, luciferase assay, ChIP assay, and bioinformatics analysis were performed to reveal the underlying mechanisms. High expression of STK16 was observed in LUAD tissues and cells, and higher expression of STK16 was associated with worse prognosis. Silencing STK16 expression inhibited cell proliferation and promoted apoptosis via the AKT1 pathway.Exosomes from M1 macrophages inhibited viability and promoted apoptosis by inhibiting STK16. Moreover, miR-181a-5p is the functional molecule in M1 macrophagederived exosomes and plays a vital role in inhibiting cell proliferation and promoting apoptosis by targeting ETS1 and STK16. Hence, exosomes derived from M1 macrophages were capable of inhibiting viability and promoting apoptosis in LUAD via the miR-181a-5p/ETS1/STK16 axis.

Exosomal miR‐181a‐5p derived from SAOS‐2 cells promotes macrophages M2 polarization by targeting RORA

“…15 Consistently, the results of the present study showed Interestingly, it was also reported that cancer-associated fibroblast, another major cell in TME, delivered exosomal miR-181a-5p to a lung cancer cell to promote cell apoptosis. 13 From these results, it could be inferred that miR-181a-5p play as a critical regulator in the cross talk of tumor cells and TME.…”

“…It was demonstrated that miR-181a-5p acted as an oncogene in multiple cancers. 13,26 For instance, miR-181a-5p was known to be upregulated in osteosarcoma and play as a tumorpromoting role via accelerating cell proliferation and decreasing cell apoptosis. 15 Consistently, the results of the present study showed Interestingly, it was also reported that cancer-associated fibroblast, another major cell in TME, delivered exosomal miR-181a-5p to a lung cancer cell to promote cell apoptosis.…”

“…12 A recent study reported that exosomal miR-181a-5p from M1-polarized macrophages-promoted apoptosis in lung cancer. 13 Zang et al indicated that miR-181a-5p was overexpressed in osteosarcoma and could promote proliferation and metastasis. 14 Moreover, it was also highlighted that miR-181a-5p was upregulated in osteosarcoma tissue and cell lines, and high miR-181a-5p expression was correlated with poor prognosis.…”

Exosomes Derived from Immune Cells: The New Role of Tumor Immune Microenvironment and Tumor Therapy

“… 72 M1-Exos can carry miR-181a-5p to target ETS1 to inhibit the expression of STK16 in tumor cells, thereby reducing cell viability and promoting apoptosis of lung adenocarcinoma cells. 73 In addition, M1-Exos can also carry miR-16-5p to reduce the expression of PD-L1 in gastric cancer cells, thus reducing the inhibitory effect of immune checkpoints on T cells and promoting the activation and killing ability of T cells. 74 Chiara cianciaruso et al collected EVs released from TAM (TAM-EV) of mice and performed quantitative, proteomic, and lipidomic analyses of them.…”

Macrophage-Derived Small Extracellular Vesicles in Multiple Diseases: Biogenesis, Function, and Therapeutic Applications

“…Serine/threonine kinase 16 (STK16), a membrane-associated kinase, is involved in the regulation of cell proliferation, apoptosis, sEV signaling pathways, and metabolism ( Wang et al, 2019b ). MiRNA-181a-5p delivered by M1-sEVs inhibit the expression of STK16 by targeting ETS1 to regulate cell viability and apoptosis in lung adenocarcinoma (LUAD), while STK16 silencing significantly reduces the mass of nodules in tumor models, thus promoting the apoptosis of LUAD cells ( Wang et al, 2022a ). Serum miRNA-181a-5p was considered a potential noninvasive biomarker for the diagnosis and prognosis of patients with non-small cell lung cancer (NSCLC), while a further argument may be needed.…”