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.

Graphical abstract

中文翻译：

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含有 miR-222-3p 的巨噬细胞来源的细胞外囊泡通过 TSC1 介导的 mTOR/AKT/PI3K 通路赋予胰腺癌吉西他滨耐药性

吉西他滨耐药性限制了化疗的疗效，并对治疗结果构成了挑战。因此，我们的目的是阐明 M2 巨噬细胞来源的细胞外囊泡 (M2 MDE) 传递的 miR-222-3p 在胰腺癌 (PCa) 化疗耐药中的作用的下游机制。我们分离了小鼠巨噬细胞，并将其极化为 M2 表型，EV 就是从中衍生出来的。miR-222-3p 在 M2 MDE 中高表达。M2 MDE 被 PCa 细胞内化。用吉西他滨处理过表达 miR-222-3p 的 M2 MDE，并与 PCa 细胞共培养进行体外实验。与富含 miR-222-3p 的 M2 MDE 共培养可抑制对吉西他滨的敏感性，同时减少细胞凋亡并促进增殖。此外，将 M2 MDE 和 PCa 细胞注射到暴露于吉西他滨的小鼠体内进行体内证实。M2 MDE 递送 miR-222-3p 抑制剂可抑制肿瘤生长并提高癌细胞对吉西他滨的敏感性。此外，miR-222-3p 可靶向并抑制 TSC1 表达，而 miR-222-3p 则激活 PI3K/AKT/mTOR 通路。总之，含有 miR-222-3p 的 M2 MDE 通过 TSC1 抑制和 PI3K/AKT/mTOR 通路的激活增强 PCa 的化疗耐药性。

图形概要