Abstract
Gemcitabine resistance limits the efficacy of chemotherapy and maintains a challenge for treatment outcomes. Therefore, we aimed to clarify the downstream mechanisms underlying the role of miR-222-3p delivered by M2 macrophage-derived extracellular vesicles (M2 MDEs) in the chemoresistance of pancreatic cancer (PCa). We separated the mouse macrophages and polarized them to M2 phenotypes, from which the EVs were derived. miR-222-3p was highly expressed in M2 MDEs. M2 MDEs were internalized by PCa cells. miR-222-3p overexpressing M2 MDEs were treated with gemcitabine and co-cultured with PCa cells for in vitro experiments. Co-culture with M2 MDEs enriched with miR-222-3p suppressed the sensitivity to gemcitabine, accompanied by diminished apoptosis and promoted proliferation. Furthermore, the M2 MDEs and PCa cells were injected to mice with gemcitabine exposure for in vivo substantiation. The delivery of miR-222-3p inhibitor by M2 MDEs suppressed tumor growth and elevated sensitivity of cancer cells to gemcitabine. Moreover, miR-222-3p was indicated to target and suppress TSC1 expression, while miR-222-3p activated the PI3K/AKT/mTOR pathway. Together, miR-222-3p-containing M2 MDEs enhance chemoresistance in PCa through TSC1 inhibition and activation of the PI3K/AKT/mTOR pathway.
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The datasets generated for this study are available on request to the corresponding author.
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YG conceived and designed research. HSW performed experiments. JXX interpreted results of experiments. SMG analyzed data and prepared figures. JC drafted paper. TP edited and revised manuscript. All authors read and approved final version of manuscript.
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Animal experiments were approved by the Animal Ethics Committee of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (Approval Number: AW2019120101) and strictly performed according to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health.
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Guo, Y., Wu, H., Xiong, J. et al. miR-222-3p-containing macrophage-derived extracellular vesicles confer gemcitabine resistance via TSC1-mediated mTOR/AKT/PI3K pathway in pancreatic cancer. Cell Biol Toxicol 39, 1203–1214 (2023). https://doi.org/10.1007/s10565-022-09736-y
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DOI: https://doi.org/10.1007/s10565-022-09736-y