来自贝勒医学院分子与细胞生物学系的两位科学家认为他们之前发现的一种称为COUP-TFII的作用因子也许可以回答哪些癌症基本上处于休眠状态,目前没有任何风险,哪些癌症需要注意观察和进行积极治疗的问题。

-2013年1月10日版《自然》

中文翻译


【译文】COUP-TFII抑制TGF-β诱导的生长障碍以促进前列腺癌发生

【译文】磷酸酶和张力蛋白同系物(PTEN)的突变或编码3-羟基磷脂酰肌醇激酶信号通路的基因组变化是人类前列腺癌中所报道的最常见的遗传突变。然而,潜在的准确机制,即伴有PTEN突变的无痛性肿瘤是如何获得转移潜能的机制目前尚不清楚。近期研究表明PTEN丢失引起的转移生长因子(TGF)-β信号的上调将形成一种生长障碍,作为驱动前列腺癌进展的防御机制,表明TGF-β信号可能是阻止PTEN介导的肿瘤发生的一种侵袭前检查点。本研究表明COUP转录因子II (COUP-TFII,又名NR2F2,核受体超家族成员之一)作为关键调控因子以抑制SMAD4依赖的转录,并且随后消除无PTEN的无痛性肿瘤中TGF-β依赖的检查点。小鼠前列腺上皮中COUP-TFII的过表达联合PTEN缺失,增加了恶性进展并产生具有强烈转移倾向的肿瘤。 COUP-TFII和SMAD4之间的功能对抗作用通过遗传工程的小鼠模型得到证实。该小鼠模型中SMAD4的条件性缺失会降低由COUP-TFII的消除而诱发的抑制性效应。前列腺癌发生中COUP-TFII的生物重要性通过患者样本分析得到证实,即COUP-TFII表达或活性与肿瘤反复和疾病进展紧密相关,而与TGF-β信号反向相关。这些发现揭示了COUP-TFII产生的TGF-β依赖性障碍的破坏对于PTEN突变的前列腺癌进展成为威胁生命的疾病是至关重要的,并且COUP-TFII将成为转移性人前列腺癌干预的潜在药物靶点。

英文原稿


[Title]: COUP-TFII inhibits TGF-β-induced growth barrier to promote prostate tumorigenesis

[Authors]:Jun Qin,1 San-Pin Wu,1 Chad J. Creighton,2 Fangyan Dai,1, 3 Xin Xie,1 Chiang-Min Cheng,1 Anna Frolov,4 Gustavo Ayala,4, 7 Xia Lin,3 Xin-Hua Feng,1, 3 Michael M. Ittmann,4 Shaw-Jenq Tsai,1, 5 Ming-Jer Tsai1, 6 & Sophia Y. Tsai1, 6

[Abstract]Mutations in phosphatase and tensin homologue (PTEN) or genomic alterations in the phosphatidylinositol-3-OH kinase-signalling pathway are the most common genetic alterations reported in human prostate cancer. However, the precise mechanism underlying how indolent tumours with PTEN alterations acquire metastatic potential remains poorly understood. Recent studies suggest that upregulation of transforming growth factor (TGF)-β signalling triggered by PTEN loss will form a growth barrier as a defence mechanism to constrain prostate cancer progression, underscoring that TGF-β signalling might represent a pre-invasive checkpoint to prevent PTEN-mediated prostate tumorigenesis. Here we show that COUP transcription factor II (COUP-TFII, also known as NR2F2), a member of the nuclear receptor superfamily, serves as a key regulator to inhibit SMAD4-dependent transcription, and consequently overrides the TGF-β-dependent checkpoint for PTEN-null indolent tumours. Overexpression of COUP-TFII in the mouse prostate epithelium cooperates with PTEN deletion to augment malignant progression and produce an aggressive metastasis-prone tumour. The functional counteraction between COUP-TFII and SMAD4 is reinforced by genetically engineered mouse models in which conditional loss of SMAD4 diminishes the inhibitory effects elicited by COUP-TFII ablation. The biological significance of COUP-TFII in prostate carcinogenesis is substantiated by patient sample analysis, in which COUP-TFII expression or activity is tightly correlated with tumour recurrence and disease progression, whereas it is inversely associated with TGF-β signalling. These findings reveal that the destruction of the TGF-β-dependent barrier by COUP-TFII is crucial for the progression of PTEN-mutant prostate cancer into a life-threatening disease, and supports COUP-TFII as a potential drug target for the intervention of metastatic human prostate cancer.

原文地址

http://www.nature.com/nature/journal/v493/n7431/full/nature11674.html

本站声明: 生物文库所有文章欢迎转载,所有文章未说明,均属于原创,转载均请注明出处。
本文链接: http://www.bioku.cn/201303/nature-coup-tfii-tgf-%ce%b2-prostate-tumorigenesis/
版权所有: 生物文库 - 生物医学、生物技术核心期刊文摘

留言


1 − 一 =


沪ICP备12028140号
点击这里给我发消息   点击这里给我发消息