Corrigendum: A miRNA-145/TGF-β1 negative feedback loop regulates the cancer-associated fibroblast phenotype.
Corrigendum: A miRNA-145/TGF-β1 negative feedback loop regulates the cancer-associated fibroblast phenotype.
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DOI：
10.1093/carcin/bgy083
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发表时间：
2018-07
期刊：
影响因子：
4.7
通讯作者：
G. Melling;Sarah E Flannery;S. A. Abidin;Hannah Clemmens;Priyanka Prajapati;E. Hinsley;S. Hunt;J. Catto;R. Coletta;M. Mellone;G. Thomas;E. K. Parkinson;S. Prime;I. Paterson;D. Buttle;D. Lambert
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文献类型：
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作者：
G. Melling;Sarah E Flannery;S. A. Abidin;Hannah Clemmens;Priyanka Prajapati;E. Hinsley;S. Hunt;J. Catto;R. Coletta;M. Mellone;G. Thomas;E. K. Parkinson;S. Prime;I. Paterson;D. Buttle;D. Lambert
癌细胞向局部和远处扩散取决于恶性细胞与其周围的细胞和非细胞成分（统称为肿瘤微环境）之间复杂而鲜为人知的相互作用。肿瘤微环境中最丰富的细胞类型之一是成纤维细胞，它会被TGF-β1等局部来源的信号破坏，并获得一种改变的异质表型（癌症相关成纤维细胞，CAF），支持肿瘤细胞的侵袭和转移。开发针对肿瘤间质的新疗法的努力受到对CAF发展机制了解不足的阻碍。在这里，我们研究了microRNA对实验衍生的CAF的发展的贡献，并将其与肿瘤衍生的CAF中观察到的变化联系起来。原代正常人成纤维细胞暴露于TGF-β1导致获得肌成纤维细胞caf样表型。这与miR-145的表达增加有关，miR-145是一种预测TGF-β信号通路多种成分的miRNA。miR-145在口腔癌来源的CAF中也过表达。过表达miR-145阻断TGF-β1诱导的肌成纤维细胞分化，并使CAF恢复到正常的成纤维细胞表型。我们得出结论，miR-145是CAF表型的关键调节因子，在负反馈回路中抑制肌成纤维细胞特征的获得，这是CAF与不良疾病结局相关的一个关键特征。
The dissemination of cancer cells to local and distant sites depends on a complex and poorly understood interplay between malignant cells and the cellular and non-cellular components surrounding them, collectively termed the tumour microenvironment. One of the most abundant cell types of the tumour microenvironment is the fibroblast, which becomes corrupted by locally derived cues such as TGF-β1 and acquires an altered, heterogeneous phenotype (cancer-associated fibroblasts, CAF) supportive of tumour cell invasion and metastasis. Efforts to develop new treatments targeting the tumour mesenchyme are hampered by a poor understanding of the mechanisms underlying the development of CAF. Here, we examine the contribution of microRNA to the development of experimentally-derived CAF and correlate this with changes observed in CAF derived from tumours. Exposure of primary normal human fibroblasts to TGF-β1 resulted in the acquisition of a myofibroblastic CAF-like phenotype. This was associated with increased expression of miR-145, a miRNA predictedin silicoto target multiple components of the TGF-β signalling pathway. miR-145 was also overexpressed in CAF derived from oral cancers. Overexpression of miR-145 blocked TGF-β1-induced myofibroblastic differentiation and reverted CAF towards a normal fibroblast phenotype. We conclude that miR-145 is a key regulator of the CAF phenotype, acting in a negative feedback loop to dampen acquisition of myofibroblastic traits, a key feature of CAF associated with poor disease outcome.