miR-21 Induces Myofibroblast Differentiation and Promotes the Malignant Progression of Breast Phyllodes Tumors
miR-21 Induces Myofibroblast Differentiation and Promotes the Malignant Progression of Breast Phyllodes Tumors
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miR-21诱导肌成纤维细胞分化并促进乳腺叶状肿瘤恶性进展
DOI：
10.1158/0008-5472.can-14-0125
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发表时间：
2014-08-16
期刊：
影响因子：
11.2
通讯作者：
Liu, Qiang
中科院分区：
文献类型：
--
作者：
Gong, Chang;Nie, Yan;Liu, Qiang
乳腺的叶状肿瘤，即使在组织学上被诊断为良性的，也可以局部复发并有转移的可能。组织学标志物在预测叶状肿瘤的临床行为方面的价值有限。目前尚不清楚是什么导致了叶状肿瘤的恶性进展。我们发现，在叶状肿瘤的恶性进展过程中，肌成纤维细胞标志物α-平滑肌肌动蛋白(α-SMA)、成纤维细胞激活蛋白(FAP)和基质细胞衍生因子-1(SDF-1)的表达逐渐增加。基因芯片显示miR-21是与良性叶状肿瘤相比在恶性叶状肿瘤中上调最显著的microRNAs之一。此外，miR-21表达的增加主要局限于α-SMA阳性的肌成纤维细胞。更重要的是，α-SMA和miR-21是复发和转移的独立预测因子，其复发预测价值优于组织学分级。此外，miR-21模拟物促进了α-SMA、FAP和SDF-1的表达，而miR-21反义寡核苷酸则抑制了其表达，并促进了叶状肿瘤原代基质细胞的增殖和侵袭。MiR-21诱导肌成纤维细胞分化的能力是通过其对Smad7和PTEN的调控而实现的，而Smad7和PTEN分别调控着细胞的迁移和增殖。在乳腺叶状瘤移植瘤中，miR-21促进肿瘤生长，诱导肌成纤维细胞分化，促进转移。这项研究表明，肌成纤维细胞分化在由miR-21增加所驱动的叶状肿瘤的恶性进展中起着重要作用。(C)2014年AACR。
Phyllodes tumors of breast, even histologically diagnosed as benign, can recur locally and have metastatic potential. Histologic markers only have limited value in predicting the clinical behavior of phyllodes tumors. It remains unknown what drives the malignant progression of phyllodes tumors. We found that the expression of myofibroblast markers, alpha-smooth muscle actin (alpha-SMA), fibroblast activation protein (FAP), and stromal cell-derived factor-1 (SDF-1), is progressively increased in the malignant progression of phyllodes tumors. Microarray showed that miR-21 was one of the most significantly upregulated microRNAs in malignant phyllodes tumors compared with benign phyllodes tumors. In addition, increased miR-21 expression was primarily localized to alpha-SMA-positive myofibroblasts. More importantly, alpha-SMA and miR-21 are independent predictors of recurrence and metastasis, with their predictive value of recurrence better than histologic grading. Furthermore, miR-21 mimics promoted, whereas miR-21 antisense oligos inhibited, the expression of alpha-SMA, FAP, and SDF-1, as well as the proliferation and invasion of primary stromal cells of phyllodes tumors. The ability of miR-21 to induce myofibroblast differentiation was mediated by its regulation on Smad7 and PTEN, which regulate the migration and proliferation, respectively. In breast phyllodes tumor xenografts, miR-21 accelerated tumor growth, induced myofibroblast differentiation, and promoted metastasis. This study suggests an important role of myofibroblast differentiation in the malignant progression of phyllodes tumors that is driven by increased miR-21. (C) 2014 AACR.