Fibulin-5 initiates epithelial-mesenchymal transition (EMT) and enhances EMT induced by TGF-beta in mammary epithelial cells via a MMP-dependent mechanism.
Fibulin-5 initiates epithelial-mesenchymal transition (EMT) and enhances EMT induced by TGF-beta in mammary epithelial cells via a MMP-dependent mechanism.
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DOI：
10.1093/carcin/bgn199
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发表时间：
2008-12
期刊：
影响因子：
4.7
通讯作者：
Schiemann WP
中科院分区：
文献类型：
--
作者：
Lee YH;Albig AR;Regner M;Schiemann BJ;Schiemann WP
上皮-间质转化（Epithelial-mesenchymal transition， EMT）是调节组织发育、重塑和修复的正常生理过程；然而，异常的EMT也会引起人类疾病的发展，包括肺纤维化、类风湿关节炎和癌细胞转移。转化生长因子-β (TGF-β)是正常乳腺上皮细胞（MECs）中EMT的主要调节因子，其中这种多效细胞因子也作为乳腺肿瘤发生的有效抑制因子。相反，恶性mec通常会对TGF-β介导的细胞停滞产生抗性，并在TGF-β的刺激下发展出增殖、侵袭和转移的能力。因此，确定TGF-β如何促进EMT可能为靶向TGF-β在人类乳腺癌中的致癌活性提供新的见解。通过监测肌动蛋白细胞骨架和EMT的各种标志物的变化，我们在这里发现TGF-β基因靶点纤维蛋白-5 （FBLN5）启动EMT并增强TGF-β诱导的EMT。正常mec中FBLN5转录本较少，而TGF-β诱导的mec中，FBLN5 mRNA表达显著上调，表明EMT和mec去分化覆盖了极化mec中FBLN5表达的抑制。我们还发现，FBLN5刺激MMP的表达和活性，导致MEC侵袭和EMT， Twist表达升高，E-cadherin表达降低。最后，FBLN5促进正常和恶性mec的非锚定生长，并促进小鼠4T1肿瘤的生长。综上所述，这些发现确定了FBLN5在乳腺癌发生和进展中的一种新的EMT和肿瘤促进功能。
Epithelial-mesenchymal transition (EMT) is normal physiological process that regulates tissue development, remodeling, and repair; however, aberrant EMT also elicits disease development in humans, including lung fibrosis, rheumatoid arthritis, and cancer cell metastasis. Transforming growth factor-β (TGF-β) is a master regulator of EMT in normal mammary epithelial cells (MECs), wherein this pleiotropic cytokine also functions as a potent suppressor of mammary tumorigenesis. In contrast, malignant MECs typically evolve resistance to TGF-β-mediated cytostasis and develop the ability to proliferate, invade, and metastasize when stimulated by TGF-β. It therefore stands to reason that establishing how TGF-β promotes EMT may offer new insights into targeting the oncogenic activities of TGF-β in human breast cancers. By monitoring alterations in the actin cytoskeleton and various markers of EMT, we show here that the TGF-β gene target, fibulin-5 (FBLN5), initiates EMT and enhances that induced by TGF-β. While normal MECs contain few FBLN5 transcripts, those induced to undergo EMT by TGF-β show significant upregulation of FBLN5 mRNA, suggesting that EMT and the dedifferentiation of MECs overrides the repression of FBLN5 expression in polarized MECs. We also show that FBLN5 stimulated MMP expression and activity, leading to MEC invasion and EMT, to elevated Twist expression, and to reduced E-cadherin expression. Finally, FBLN5 promoted anchorage-independent growth in normal and malignant MECs, as well as enhanced the growth of 4T1 tumors in mice. Taken together, these findings identify a novel EMT and tumor promoting function for FBLN5 in developing and progressing breast cancers.
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影响因子：
3.1
作者：
Kapetanopoulos, A;Fresser, F;Utermann, G
通讯作者：
Utermann, G
影响因子：
11.2
作者：
Albig, AR;Neil, JR;Schiemann, WP
通讯作者：
Schiemann, WP
影响因子：
30.8
作者：
Liu, XQ;Zhao, Y;Li, TS
通讯作者：
Li, TS
DOI：
10.1517/14796694.1.1.23
发表时间：
2005-02-01
期刊：
Future oncology (London, England)
影响因子：
--
作者：
Albig, Allan R;Schiemann, William P
通讯作者：
Schiemann, William P
影响因子：
20.1
作者：
Kowal, RC;Richardson, JA;Olson, EN
通讯作者：
Olson, EN