Synaptopodin-2 suppresses metastasis of triple-negative breast cancer via inhibition of YAP/TAZ activity
Synaptopodin-2 suppresses metastasis of triple-negative breast cancer via inhibition of YAP/TAZ activity
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Synaptopodin-2 通过抑制 YAP/TAZ 活性抑制三阴性乳腺癌的转移
DOI：
10.1002/path.4995
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发表时间：
2018-01-01
影响因子：
7.3
通讯作者：
Lin, Chuyong
中科院分区：
文献类型：
--
作者：
Liu, Junling;Ye, Liping;Lin, Chuyong
三阴性乳腺癌（TNBC）是乳腺癌中最具侵袭性的亚型，具有很高的远处转移发生率;然而，这种频繁复发的潜在机制仍不清楚。在此，我们表明，synaptopodin-2（SYNPO 2），一个假定的肿瘤抑制剂在侵袭性癌症，是经常下调TNBC的SYNPO 2启动子的甲基化。SYNPO 2低表达与5年转移复发显著相关，并预测乳腺癌患者预后较差。SYNPO 2的重新引入抑制了TNBC细胞在体内的侵袭和自发转移。引人注目的是，SYNPO 2的下调对于维持TNBC细胞中的干细胞样性质是必不可少的，导致有效的远距离定植和转移生长。此外，我们证明SYNPO 2通过稳定LATS 2蛋白来抑制雅普和TAZ的活性，并且YAP-S127 A的转导消除了SYNPO 2在转移中的抑制作用。最后，乳腺癌患者标本的免疫组织化学（IHC）分析表明SYNPO 2-LATS 2-雅普轴具有临床相关性。这些发现揭示了SYNPO 2通过抑制雅普/TAZ在TNBC转移中的抑制作用，并表明SYNPO 2可能提供潜在的预后标记物和新的治疗策略。版权所有（C）2017大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer, with a high incidence of distant metastasis; however, the underlying mechanism for this frequent recurrence remains unclear. Herein, we show that synaptopodin-2 (SYNPO2), a putative tumour suppressor in aggressive cancer, is frequently downregulated in TNBC by methylation of the promoter of SYNPO2. Low expression levels of SYNPO2 correlated significantly with 5-year metastatic relapse, and predicted poorer prognosis in breast cancer patients. Reintroduction of SYNPO2 inhibited the invasion and spontaneous metastasis of TNBC cells in vivo. Strikingly, downregulation of SYNPO2 is essential for the maintenance of stem cell-like properties in TNBC cells, leading to efficient distant colonization and metastasis outgrowth. Moreover, we demonstrate that SYNPO2 inhibits the activities of YAP and TAZ by stabilizing LATS2 protein, and transduction of YAP-S127A abrogates the repressive role of SYNPO2 in metastasis. Finally, immunohistochemical (IHC) analysis of breast cancer patient specimens indicated that the SYNPO2-LATS2-YAP axis is clinically relevant. These findings uncover a suppressive role of SYNPO2 in TNBC metastasis via inhibition of YAP/TAZ, and suggest that SYNPO2 might provide a potential prognosis marker and novel therapeutic strategy. Copyright (C) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.