Department of Breast and Thyroid Surgery, The Affiliated Shapingba Hospital of Chongqing University, Chongqing 400030, P.R. China.
Shanxi Medical University, Taiyuan, Shanxi 030607, P.R. China.
Int J Oncol. 2022 Oct;61(4). doi: 10.3892/ijo.2022.5416. Epub 2022 Sep 7.
Macrophages are principal immune cells with a high plasticity in the human body that can differentiate under different conditions in the tumor microenvironment to adopt two polarized phenotypes with opposite functions. Therefore, converting macrophages from the immunosuppressive phenotype (M2) to the inflammatory phenotype (M1) is considered a promising therapeutic strategy for cancer. However, the molecular mechanisms underlying this conversion process have not yet been completely elucidated. In recent years, microRNAs (miRNAs or miRs) have been shown to play key roles in regulating macrophage polarization through their ability to modulate gene expression. In the present study, it was found that miR‑382 expression was significantly downregulated in tumor‑associated macrophages (TAMs) and M2‑polarized macrophages in breast cancer. , macrophage polarization toward the M2 phenotype and M2‑type cytokine release were inhibited by transfection with miR‑382‑overexpressing lentivirus. Similarly, the overexpression of miR‑382 inhibited the ability of TAMs to promote the malignant behaviors of breast cancer cells. In addition, peroxisome proliferator‑activated receptor γ coactivator‑1α (PGC‑1α) was identified as the downstream target of miR‑382 and it was found that PGC‑1α affected macrophage polarization by altering the metabolic status. The ectopic expression of PGC‑1α restored the phenotype and cytokine secretion of miR‑382‑overexpressing macrophages. Furthermore, PGC‑1α expression reversed the miR‑382‑induced changes in the metabolic state of TAMs and the effects of TAMs on breast cancer cells. Of note, the growth and metastasis of 4T1 cells were inhibited by miR‑382‑overexpressing TAMs. Taken together, the results of the present study suggest that miR‑382 may alter the metabolic status of macrophages by targeting PGC‑1α, thereby decreasing the proportion of TAMs with the M2 phenotype, and inhibiting the progression and metastasis of breast cancer.
巨噬细胞是人体内主要的免疫细胞，具有很高的可塑性，可在肿瘤微环境中的不同条件下分化为两种具有相反功能的极化表型。因此，将巨噬细胞从免疫抑制表型（M2）转化为炎症表型（M1）被认为是癌症的一种有前途的治疗策略。然而，这种转化过程的分子机制尚未完全阐明。近年来，研究表明 microRNAs（miRNAs 或 miRs）通过调节基因表达在调节巨噬细胞极化中发挥关键作用。在本研究中，发现 miR-382 在乳腺癌相关巨噬细胞（TAMs）和 M2 极化巨噬细胞中的表达显著下调。通过转染 miR-382 过表达慢病毒，抑制巨噬细胞向 M2 表型极化和 M2 型细胞因子释放。同样，miR-382 的过表达抑制了 TAMs 促进乳腺癌细胞恶性行为的能力。此外，过氧化物酶体增殖物激活受体 γ 共激活因子 1α（PGC-1α）被鉴定为 miR-382 的下游靶标，发现 PGC-1α 通过改变代谢状态影响巨噬细胞极化。PGC-1α 的异位表达恢复了 miR-382 过表达巨噬细胞的表型和细胞因子分泌。此外，PGC-1α 表达逆转了 miR-382 诱导的 TAMs 代谢状态变化以及 TAMs 对乳腺癌细胞的影响。值得注意的是，miR-382 过表达 TAMs 抑制了 4T1 细胞的生长和转移。综上所述，本研究结果表明，miR-382 可能通过靶向 PGC-1α 改变巨噬细胞的代谢状态，从而减少具有 M2 表型的 TAMs 比例，抑制乳腺癌的进展和转移。
