Dicer reprograms stromal fibroblasts to a pro-inflammatory and tumor-promoting phenotype in ovarian cancer
Dicer reprograms stromal fibroblasts to a pro-inflammatory and tumor-promoting phenotype in ovarian cancer
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Dicer 将卵巢癌中的基质成纤维细胞重编程为促炎和促肿瘤表型
DOI：
10.1016/j.canlet.2017.11.026
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发表时间：
2018
期刊：
影响因子：
9.7
通讯作者：
Gao Qinglei
中科院分区：
文献类型：
--
作者：
Yang Zongyuan;Jin Ping;Xu Sen;Zhang Taoran;Yang Xin;Li Xiaoting;Wei Xiao;Sun Chaoyang;Chen Gang;Ma Ding;Gao Qinglei
炎症和宿主间质活化显著促进卵巢癌（OC）的发生和恶性进展。然而，它们之间复杂的相互作用在很大程度上是未知的。在此，我们发现肿瘤抑制基因Dicer在卵巢肿瘤间质中反常地过表达，并诱导成纤维细胞活化和间质炎症。Dicer将正常成纤维细胞转化为癌相关成纤维细胞（CAF）样状态，其在形态学上扩散并在功能上活化以促进肿瘤侵袭和转移。Dicer的减弱阻碍了CAF特征，减少了基质炎症和成纤维细胞在支持肿瘤生长中的作用。此外，Dicer驱动成纤维细胞中“炎症信号”的表达，可用于区分正常和癌性基质并预测OC患者的生存期。最后，核因子κ B（NFκB）信号被证明是通过microRNA（miR）-6780 b对成纤维细胞活化和间质炎症的Dicer效应的原因。我们的研究代表了第一份描述Dicer在肿瘤间质中表达和功能的报告，并强调了其在这种情况下的促转移作用。此外，我们认为Dicer-miR 6780 b-NF κB级联是基质导向OC治疗中有吸引力的选择靶点。
Inflammation and host stromal activation contribute significantly to ovarian cancer (OC) initiation and malignant progression. However, the complex reciprocal interactions between them are largely unknown. Here, we discovered that the tumor suppressor gene Dicer was paradoxically overexpressed in ovarian tumor stroma, and induced fibroblast activation and stromal inflammation. Dicer transformed normal fibroblasts to a carcinoma-associated fibroblast (CAF)-like state, which was morphologically spread out and functionally activated to fuel tumor invasion and metastasis. Attenuation of Dicer hampered CAF characteristics, diminished stromal inflammation and the role of fibroblasts in supporting tumor growth. Moreover, Dicer drove the expression of an “inflammatory signature” in fibroblasts that could be used to discriminate normal and cancerous stroma and predict the survival of patients with OC. Finally, the nuclear factor κ B (NFκB) signaling was demonstrated to be responsible for Dicer effect on fibroblast activation and stromal inflammation, through microRNA (miR)-6780b. Our study represents the first report that characterizes Dicer expression and function in the tumor stroma, and highlights its pro-metastatic role in this context. Additionally, we suggest that the Dicer-miR6780b-NFκB cascade is an attractive target of choice in stroma-oriented OC therapy.