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外源性表皮生长因子受体和雄激素受体通过细胞外囊泡的核运输。

Nuclear transportation of exogenous epidermal growth factor receptor and androgen receptor via extracellular vesicles.

作者信息

Read Jolene, Ingram Alistair, Al Saleh Hassan A, Platko Khrystyna, Gabriel Kathleen, Kapoor Anil, Pinthus Jehonathan, Majeed Fadwa, Qureshi Talha, Al-Nedawi Khalid

机构信息

Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Canada.

Medical School, University of Ottawa, Ottawa, Canada.

出版信息

Eur J Cancer. 2017 Jan;70:62-74. doi: 10.1016/j.ejca.2016.10.017. Epub 2016 Nov 22.

Abstract

Epidermal growth factor receptor (EGFR) plays a central role in the progression of several human malignancies. Although EGFR is a membrane receptor, it undergoes nuclear translocation, where it has a distinct signalling pathway. Herein, we report a novel mechanism by which cancer cells can directly transport EGFR to the nucleus of other cells via extracellular vesicles (EVs). The transported receptor is active and stimulates the nuclear EGFR pathways. Interestingly, the translocation of EGFR via EVs occurs independently of the nuclear localisation sequence that is required for nuclear translocation of endogenous EGFR. Also, we found that the mutant receptor EGFRvIII could be transported to the nucleus of other cells via EVs. To assess the role of EVs in the regulation of an actual nuclear receptor, we studied the regulation of androgen receptor (AR). We found that full-length AR and mutant variant ARv7 are secreted in EVs derived from prostate cancer cell lines and could be transported to the nucleus of AR-null cells. The EV-derived AR was able to bind the androgen-responsive promoter region of prostate specific antigen, and recruit RNA Pol II, an indication of active transcription. The nuclear-translocated AR via EVs enhanced the proliferation of acceptor cells in the absence of androgen. Finally, we provide evidence that nuclear localisation of AR could occur in vivo via orthotopically-injected EVs in male SCID mice prostate glands. To our knowledge, this is the first study showing the nuclear translocation of nuclear receptors via EVs, which significantly extends the role of EVs as paracrine transcriptional regulators.

摘要

表皮生长因子受体(EGFR)在多种人类恶性肿瘤的进展中起着核心作用。尽管EGFR是一种膜受体,但它会发生核转位,在细胞核中有一条独特的信号通路。在此,我们报告一种新机制,癌细胞可通过细胞外囊泡(EVs)将EGFR直接转运至其他细胞的细胞核。转运的受体具有活性,并能刺激细胞核内的EGFR信号通路。有趣的是,EGFR通过EVs的转位独立于内源性EGFR核转位所需的核定位序列。此外,我们发现突变受体EGFRvIII也可通过EVs转运至其他细胞的细胞核。为评估EVs在调节实际核受体中的作用,我们研究了雄激素受体(AR)的调节。我们发现全长AR和突变变体ARv7分泌于源自前列腺癌细胞系的EVs中,并可转运至AR缺失细胞的细胞核。EVs来源的AR能够结合前列腺特异性抗原的雄激素反应性启动子区域,并募集RNA聚合酶II,这表明存在活跃转录。通过EVs进行核转位的AR在无雄激素的情况下增强了受体细胞的增殖。最后,我们提供证据表明AR在雄性SCID小鼠前列腺中通过原位注射的EVs可在体内发生核定位。据我们所知,这是第一项显示核受体通过EVs进行核转位的研究,这显著扩展了EVs作为旁分泌转录调节因子的作用。

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