敲低肝癌细胞分泌的外泌体 PSMA5 通过阻断 JAK2/STAT3 信号转导控制巨噬细胞极化抑制肿瘤进展。
Knockdown of liver cancer cell-secreted exosomal PSMA5 controls macrophage polarization to restrain cancer progression by blocking JAK2/STAT3 signaling.
机构信息
Department of Hepatobiliary and Pancreatic Surgery, Ningbo No.2 Hospital, Ningbo, Zhejiang, China.
Department of Plastic Surgery, Ningbo No.2 Hospital, Ningbo, Zhejiang, China.
出版信息
Immun Inflamm Dis. 2024 Feb;12(2):e1146. doi: 10.1002/iid3.1146.
INTRODUCTION
Tumor-associated macrophages, a major component of the tumor microenvironment, undergo polarization into M2 macrophages (M2), and thereby exert an immunosuppressive effect to induce cancer metastasis. This study strives to uncover a molecular mechanism underlying this event in hepatocellular carcinoma (HCC).
METHODS
Proteasome subunit alpha 5 (PSMA5) expression in liver hepatocellular carcinoma (LIHC) tissues and its association with LIHC patients were predicted using StarBase. PSMA5 level in human HCC cells was manipulated via transfection. Exosomes were isolated from HCC cells, and internalized into macrophages which were cocultured with HCC cells. Exosome internalization was observed after fluorescence labeling. HCC cell migration and invasion were evaluated by wound healing and Transwell assays. Xenograft assay was performed to investigate the role of PSMA5 in in vitro tumorigenesis. M2 polarization was assessed by enzyme-linked immunosorbent assay, quantitative reverse transcription polymerase chain reaction, and immunohistochemistry. PSMA5 expression in exosomes and Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) activation in macrophages and tumors were detected by Western blot analysis.
RESULTS
High PSMA5 expression was observed in LIHC tissues and associated with compromised survival of LIHC patients. PSMA5 knockdown inhibited HCC cell migration and invasion. PSMA5 knockdown in HCC cells downregulated PSMA5 level in exosomes from these HCC cells. HCC cell-isolated exosomes were successfully internalized into macrophages, and facilitated M2 polarization and JAK2/STAT3 pathway activation. HCC cell-secreted exosomal PSMA5 knockdown inhibited the exosome-induced effect on macrophages, and attenuated the promotion induced by exosome-treated macrophages on HCC cell migration/invasion and tumorigenesis along with in vivo M2 polarization and JAK2/STAT3 pathway activation.
CONCLUSION
HCC cell-secreted exosomal PSMA5 knockdown hinders M2 polarization to suppress cancer progression by restraining JAK2/STAT3 signaling.
简介
肿瘤相关巨噬细胞（TAMs）是肿瘤微环境的主要组成部分，可极化为 M2 巨噬细胞（M2），从而发挥免疫抑制作用，诱导癌症转移。本研究旨在揭示肝癌（HCC）中这一事件的分子机制。
方法
使用 StarBase 预测了肝癌组织中蛋白酶体亚基α 5（PSMA5）的表达及其与 HCC 患者的关系。通过转染来操纵人 HCC 细胞中的 PSMA5 水平。从 HCC 细胞中分离出外泌体，并将其内化到与 HCC 细胞共培养的巨噬细胞中。用荧光标记观察外泌体的内化。通过划痕愈合和 Transwell 测定评估 HCC 细胞的迁移和侵袭。进行异种移植实验以研究 PSMA5 在体外肿瘤发生中的作用。通过酶联免疫吸附测定、定量逆转录聚合酶链反应和免疫组织化学评估 M2 极化。通过 Western blot 分析检测外泌体中的 PSMA5 表达和巨噬细胞和肿瘤中的 Janus 激酶 2（JAK2）/信号转导和转录激活因子 3（STAT3）激活。
结果
PSMA5 在 HCC 组织中高表达，并与 HCC 患者的生存状况恶化相关。PSMA5 敲低抑制 HCC 细胞的迁移和侵袭。HCC 细胞中的 PSMA5 敲低下调了这些 HCC 细胞来源的外泌体中的 PSMA5 水平。HCC 细胞分离的外泌体成功地被内化到巨噬细胞中，并促进了 M2 极化和 JAK2/STAT3 途径的激活。HCC 细胞分泌的外泌体 PSMA5 敲低抑制了外泌体对巨噬细胞的诱导作用，并减弱了外泌体处理的巨噬细胞对 HCC 细胞迁移/侵袭和肿瘤发生的促进作用，同时体内 M2 极化和 JAK2/STAT3 途径的激活。
结论
HCC 细胞分泌的外泌体 PSMA5 敲低通过抑制 JAK2/STAT3 信号抑制 M2 极化，从而抑制癌症进展。
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