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雌二醇-雌激素受体β2信号轴通过跨膜丝氨酸蛋白酶2-ETS变异体5基因融合赋予去势抵抗性前列腺癌细胞生长和迁移能力。

Estradiol-ERβ2 signaling axis confers growth and migration of CRPC cells through TMPRSS2-ETV5 gene fusion.

作者信息

Kim Hogyoung, Datta Amrita, Talwar Sudha, Saleem Sarmad N, Mondal Debasis, Abdel-Mageed Asim B

机构信息

Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana, 70112, USA.

Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, 70112, USA.

出版信息

Oncotarget. 2016 Aug 17;8(38):62820-62833. doi: 10.18632/oncotarget.11355. eCollection 2017 Sep 8.

DOI:10.18632/oncotarget.11355
PMID:28968951
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5609883/
Abstract

Estrogen receptor beta (ERβ) splice variants are implicated in prostate cancer (PC) progression; however their underlying mechanisms remain elusive. We report that non-canonical activation of estradiol (E)-ERβ2 signaling axis primes growth, colony-forming ability and migration of the androgen receptor (AR)-null castration-resistant PC (CRPC) cells under androgen-deprived conditions (ADC). The non-classical E-ERβ2 mediates phosphorylation and activation of Src-IGF-1R complex, which in turn triggers p65-dependent transcriptional upregulation of the androgen-regulated serine protease gene fusions under ADC. siRNA silencing of and/or suggests that fusions facilitates the E-ERβ induced growth and migration effects via NF-κB-dependent induction of cyclin D1 and MMP2 and MMP9 in PC-3 cells. Collectively, our results unravel the functional significance of oncogenic fusions in mediating growth and migration of E-ERβ2 signaling axis in CRPC cells. E-ERβ2 signaling axis may have significant therapeutic and prognostic implications in patients with CRPC.

摘要

雌激素受体β（ERβ）剪接变体与前列腺癌（PC）进展有关；然而，其潜在机制仍不清楚。我们报告，在雄激素剥夺条件（ADC）下，雌二醇（E）-ERβ2信号轴的非经典激活引发雄激素受体（AR）缺失的去势抵抗性PC（CRPC）细胞的生长、集落形成能力和迁移。非经典的E-ERβ2介导Src-IGF-1R复合物的磷酸化和激活，进而在ADC下触发雄激素调节的丝氨酸蛋白酶基因融合物的p65依赖性转录上调。对……和/或……的siRNA沉默表明，……融合物通过NF-κB依赖性诱导PC-3细胞中的细胞周期蛋白D1以及MMP2和MMP9促进E-ERβ诱导的生长和迁移效应。总的来说，我们的结果揭示了致癌性……融合物在介导CRPC细胞中E-ERβ2信号轴的生长和迁移方面的功能意义。E-ERβ2信号轴可能对CRPC患者具有重要的治疗和预后意义。 （注：原文中部分内容缺失，用“……”代替）

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bc5/5609883/e143021c1abd/oncotarget-08-62820-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bc5/5609883/eabe11ab50e5/oncotarget-08-62820-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bc5/5609883/32d55bb7d938/oncotarget-08-62820-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bc5/5609883/e143021c1abd/oncotarget-08-62820-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bc5/5609883/eabe11ab50e5/oncotarget-08-62820-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bc5/5609883/32d55bb7d938/oncotarget-08-62820-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bc5/5609883/e143021c1abd/oncotarget-08-62820-g003.jpg

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