Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Wujin Road 85, Shanghai, 200080, China; Institute of Urology, Shanghai Jiao Tong University, Shanghai, 200080, China.
Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Wujin Road 85, Shanghai, 200080, China; Institute of Urology, Shanghai Jiao Tong University, Shanghai, 200080, China.
Int Immunopharmacol. 2022 Jun;107:108586. doi: 10.1016/j.intimp.2022.108586. Epub 2022 Feb 25.
Tumor-associated macrophages (TAMs) are major innate immune cells that play crucial roles in prostate cancer onset and progression. Recently, increasing evidence has suggested that elevated N6-adenine methylation of mRNA is observed in prostate cancer tissues and is closely associated with a poor prognosis. However, its role in prostate cancer-associated macrophages remains poorly understood. Here, we showed that downregulation of METTL3 in prostate cancer TAMs modulated macrophages toward an M2-like phenotype and that this modulation was mediated by activation of STAT6. In addition, our data demonstrated that prostate cancer cell-derived small lipid molecule lipoxin A4 (LXA4) activated STAT6 by inhibiting METTL3. Treatment with PBP10 (an inhibitor of the LXA4 receptor) abolished the inhibition of METTL3 by LXA4 and consequently reduced the tumorigenicity of prostate cancer cells. Altogether, this work demonstrated that prostate cancer cells facilitate polarization of M2 like macrophages by releasing LXA4 via inhibiting METTL3. These findings provide new insight into the mechanism of microenvironmental regulation of macrophage polarization during prostate cancer progression.
肿瘤相关巨噬细胞（TAMs）是主要的先天免疫细胞，在前列腺癌的发生和发展中发挥着关键作用。最近，越来越多的证据表明，在前列腺癌组织中观察到 mRNA 的 N6-腺嘌呤甲基化水平升高，并且与预后不良密切相关。然而，其在前列腺癌相关巨噬细胞中的作用仍知之甚少。在这里，我们表明，下调前列腺癌 TAMs 中的 METTL3 可将巨噬细胞向 M2 样表型调节，这种调节是通过激活 STAT6 介导的。此外，我们的数据表明，前列腺癌细胞衍生的小分子脂质脂氧素 A4（LXA4）通过抑制 METTL3 来激活 STAT6。用 PBP10（LXA4 受体的抑制剂）处理可消除 LXA4 对 METTL3 的抑制作用，从而降低前列腺癌细胞的致瘤性。总之，这项工作表明，前列腺癌细胞通过释放 LXA4 抑制 METTL3 促进 M2 样巨噬细胞的极化。这些发现为前列腺癌进展过程中巨噬细胞极化的微环境调节机制提供了新的见解。
