Extracellular Vesicles Derived from SIPA1(high) Breast Cancer Cells Enhance Macrophage Infiltration and Cancer Metastasis through Myosin-9.
Extracellular Vesicles Derived from SIPA1(high) Breast Cancer Cells Enhance Macrophage Infiltration and Cancer Metastasis through Myosin-9.
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SIPA1high 乳腺癌细胞来源的细胞外囊泡通过 Myosin-9 增强巨噬细胞浸润和癌症转移
作者：
乳腺癌中信号诱导增殖相关蛋白1（SIPA 1）的高表达可能会加重癌细胞转移，但肿瘤微环境如何参与这一事件尚不清楚。在这项研究中，我们研究了SIPA 1高表达的乳腺癌细胞是否将巨噬细胞招募到肿瘤微环境中。我们还发现，细胞外囊泡（EVs）衍生自MDA-MB-231细胞显着增强巨噬细胞迁移，与SIPA 1敲低MDA-MB-231细胞在体外和体内。就其机制而言，癌细胞中的SIPA 1调节EV中的关键蛋白肌球蛋白9，并通过EV促进巨噬细胞浸润。我们证实，无论是下调SIPA 1的表达或阻断肌球蛋白-9的抑制剂，blebbistatin，导致抑制巨噬细胞浸润。这些发现有助于深入了解SIPA 1如何调节乳腺癌中的肿瘤微环境以促进肿瘤转移，并为开发乳腺癌转移的治疗方法提供基础。肿瘤细胞转移可以通过释放到肿瘤微环境中的癌细胞衍生的细胞外囊泡（EV）中所含的蛋白质进行遗传调节。在这里，我们发现浸润性乳腺导管癌组织和MDA-MB-231异种移植瘤中浸润的巨噬细胞数量与信号诱导增殖相关蛋白1（SIPA 1）的表达呈正相关。与SIPA 1敲低的MDA-MB-231细胞（231/si-EVs）相比，MDA-MB-231细胞衍生的EVs（231-EVs）在体外和体内均显著增强巨噬细胞迁移。我们发现SIPA 1促进MYH 9的转录，MYH 9编码肌球蛋白-9，并上调乳腺癌细胞及其EV中肌球蛋白-9的表达水平。我们还发现，通过下调SIPA 1表达或blebbistatin治疗来阻断肌球蛋白-9导致巨噬细胞浸润的抑制。生存分析显示，SIPA 1和MYH 9分子高表达的乳腺癌患者的无复发生存率较差（p = 0.028）。总之，SIPA 1high乳腺癌可通过富含肌球蛋白-9的EV增强巨噬细胞浸润，这可能加重乳腺癌的恶性程度。
The high expression of signal-induced proliferation-associated 1 (SIPA1) in breast cancer could aggravate cancer cell metastasis, but how the tumour microenvironment is involved in this incident is unknown. In this study, we investigated whether breast cancer cells with high SIPA1 expression recruited macrophages into the tumour microenvironment. We also found that extracellular vesicles (EVs) derived from MDA-MB-231 cells significantly enhanced macrophage migration, compared with that from SIPA1-knockdown MDA-MB-231 cells both in vitro and in vivo. In terms of the mechanism, SIPA1 in cancer cells modulated the key protein myosin-9 in EVs and promoted macrophage infiltration via EVs. We confirmed that either down-regulating SIPA1 expression or blocking myosin-9 by its inhibitor, blebbistatin, led to the suppression of macrophage infiltration. These findings contribute to a deep understanding of how SIPA1 regulates the tumour microenvironment in breast cancer to facilitate tumour metastasis and provide a basis for the development of therapeutics against breast cancer metastasis. Tumour cell metastasis can be genetically regulated by proteins contained in cancer cell-derived extracellular vesicles (EVs) released to the tumour microenvironment. Here, we found that the number of infiltrated macrophages was positively correlated with the expression of signal-induced proliferation-associated 1 (SIPA1) in invasive breast ductal carcinoma tissues and MDA-MB-231 xenograft tumours. EVs derived from MDA-MB-231 cells (231-EVs) significantly enhanced macrophage migration, compared with that from SIPA1-knockdown MDA-MB-231 cells (231/si-EVs) both in vitro and in vivo. We revealed that SIPA1 promoted the transcription of MYH9, which encodes myosin-9, and up-regulated the expression level of myosin-9 in breast cancer cells and their EVs. We also found that blocking myosin-9 by either down-regulating SIPA1 expression or blebbistatin treatment led to the suppression of macrophage infiltration. Survival analysis showed that breast cancer patients with high expression of SIPA1 and MYH9 molecules had worse relapse-free survival (p = 0.028). In summary, SIPA1high breast cancer can enhance macrophage infiltration through EVs enriched with myosin-9, which might aggravate the malignancy of breast cancer.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
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影响因子：
16
作者：
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通讯作者：
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影响因子：
11.1
作者：
Karlstetter M;Kopatz J;Aslanidis A;Shahraz A;Caramoy A;Linnartz-Gerlach B;Lin Y;Lückoff A;Fauser S;Düker K;Claude J;Wang Y;Ackermann J;Schmidt T;Hornung V;Skerka C;Langmann T;Neumann H
通讯作者：
Neumann H
影响因子：
4.6
作者：
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通讯作者：
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影响因子：
44.1
作者：
Luo P;Yan H;Chen X;Zhang Y;Zhao Z;Cao J;Zhu Y;Du J;Xu Z;Zhang X;Zeng S;Yang B;Ma S;He Q
通讯作者：
He Q