miR-221/222 activate the Wnt/β-catenin signaling to promote triple-negative breast cancer
miR-221/222 activate the Wnt/β-catenin signaling to promote triple-negative breast cancer
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miR-221/222激活Wnt/β-catenin信号传导促进三阴性乳腺癌
DOI：
10.1093/jmcb/mjy041
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发表时间：
2018-08-01
影响因子：
5.5
通讯作者：
Lin, Haifan
中科院分区：
文献类型：
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作者：
Liu, Sanhong;Wang, Zifeng;Lin, Haifan
三阴性乳腺癌（TNBC）的特征在于缺乏雌激素受体、孕激素受体和人表皮生长因子受体2的表达，是一种侵袭性形式的癌症，由于有限的治疗选择和缺乏有效的靶向疗法，其传达不可预测和不良的预后。Wnt/β-连环蛋白信号传导在TNBC中被过度激活，这促进了TNBC的进展。然而，TNBC中Wnt/β-连环蛋白活化的分子机制仍然未知。在这里，我们报告了miR-221/222在所有四种TNBC细胞系和来自患者的TNBC原发性肿瘤样品中的急剧过表达。此外，我们通过离体和异种移植实验证明，抑制TNBC细胞系（MDA-MB-231）中的miR-221/222表达抑制其增殖、活力、上皮向间充质转化和迁移;而在非TNBC细胞系（MCF 7）中表达miR-221/222促进所有上述癌症特性。miR-221/222通过直接抑制Wnt/β-连环蛋白信号通路的多种负调节因子（包括WIF 1、SFRP 2、DKK 2和AXIN 2）来激活该通路来实现这一目标。值得注意的是，miR-221/222表达水平与患者生存率呈负相关，而WIF 1、DKK 2、SFRP 2和AXIN 2表达水平与患者生存率呈正相关。最后，我们表明，抗miR-221/222显著增加了他莫昔芬/Wnt 3a治疗的凋亡细胞，但没有环磷酰胺/Wnt 3a治疗。这些结果表明，miR-221/222激活Wnt/β-catenin信号传导以促进乳腺癌的侵袭性和TNBC性质，并因此揭示了TNBC治疗的新前景。
Triple-negative breast cancer (TNBC), characterized by the lack of expression of the estrogen receptor, the progesterone receptor, and the human epidermal growth factor receptor 2, is an aggressive form of cancer that conveys unpredictable and poor prognosis due to limited treatment options and lack of effective targeted therapies. Wnt/beta-catenin signaling is hyperactivated in TNBC, which promotes the progression of TNBC. However, the molecular mechanism of Wnt/beta-catenin activation in TNBC remains unknown. Here, we report the drastic overexpression of miR-221/222 in all of four TNBC cell lines and TNBC primary tumor samples from patients. Furthermore, we demonstrate by both ex vivo and xenograft experiments that inhibiting miR-221/222 expression in a TNBC cell line (MDA-MB-231) suppresses its proliferation, viability, epithelial-to-mesenchymal transition, and migration; whereas expressing miR-221/222 in a non-TNBC line (MCF7) promotes all of the above cancer properties. miR-221/222 achieve so by directly repressing multiple negative regulators of the Wnt/beta-catenin signaling pathway, including WIF1, SFRP2, DKK2, and AXIN2, to activate the pathway. Notably, the level of miR-221/222 expression is inversely correlated whereas that of WIF1, DKK2, SFRP2, and AXIN2 expression is positively correlated with the patient survival. Last, we show that anti-miR-221/222 significantly increases apoptotic cells with tamoxifen/Wnt3a treatment but not with cyclophosphamide/Wnt3a treatment. These results demonstrate that miR-221/222 activate the Wnt/beta-catenin signaling to promote the aggressiveness and TNBC properties of breast cancers, and thus reveal a new prospect for TNBC treatment.