Wu Yunjie, Brennan Kieran, Fernández Alfonso Blanco, Mc Gee Margaret M
UCD School of Biomolecular & Biomedical Science, Conway Institute, University College Dublin (UCD), Belfield, Dublin 4, Ireland.
Flow Cytometry Core Technology, Conway Institute, University College Dublin (UCD), Belfield, Dublin 4, Ireland.
Transl Oncol. 2021 Aug;14(8):101112. doi: 10.1016/j.tranon.2021.101112. Epub 2021 May 10.
Extracellular Vesicles (EVs) are a heterogenous population of particles that play an important role in cell-cell communication in physiological and pathophysiological situations. In this study we reveal that the peptidyl prolyl isomerase Cyclophilin A (CypA) is enriched in cancer-derived EVs from a range of haematopoietic malignancies. CypA-enriched blood cancer EVs were taken up by normal monocytes independent of EV surface trypsin-sensitive proteins and potently stimulated pro-inflammatory MMP9 and IL-6 secretion. Further characterisation revealed that CypA is intravesicular, however, it is not present in all EVs derived from the haematopoietic cells, instead, it is predominantly located in high density EVs with a range of 1.15-1.18 g/ml. Furthermore, loss of CypA expression in haematological cancer cells attenuates high density EV-induced pro-inflammatory MMP9 and IL-6 secretion from monocytes. Mechanistically, we reveal that homozygous loss or siRNA knockdown of CypA expression significantly reduced the secretion of EVs in the range of 100-200 nm from blood cancer cells under normal and hypoxic conditions. Overall, this work reveals a novel role for CypA in cancer cell EV biogenesis.
细胞外囊泡（EVs）是一类异质性的颗粒群体，在生理和病理生理情况下的细胞间通讯中发挥着重要作用。在本研究中，我们发现肽基脯氨酰异构酶亲环素A（CypA）在一系列血液系统恶性肿瘤来源的癌症衍生EVs中富集。富含CypA的血液癌症EVs被正常单核细胞摄取，且不依赖于EV表面的胰蛋白酶敏感蛋白，并能有效刺激促炎性基质金属蛋白酶9（MMP9）和白细胞介素6（IL-6）的分泌。进一步的表征显示CypA位于囊泡内，然而并非所有造血细胞来源的EVs中都存在CypA，相反，它主要位于密度为1.15 - 1.18 g/ml的高密度EVs中。此外，血液系统癌细胞中CypA表达的缺失减弱了高密度EV诱导的单核细胞促炎性MMP9和IL-6的分泌。从机制上来说，我们发现CypA表达的纯合缺失或小干扰RNA（siRNA）敲低显著降低了在正常和低氧条件下血液癌细胞分泌的100 - 200 nm范围内的EVs。总的来说，这项工作揭示了CypA在癌细胞EV生物发生中的新作用。
