Antitumor effects of the antiparasitic agent ivermectin via inhibition of Yes-associated protein 1 expression in gastric cancer.
Antitumor effects of the antiparasitic agent ivermectin via inhibition of Yes-associated protein 1 expression in gastric cancer.
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DOI：
10.18632/oncotarget.22587
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发表时间：
2017-12-08
期刊：
影响因子：
--
通讯作者：
Mimori K
中科院分区：
文献类型：
--
作者：
Nambara S;Masuda T;Nishio M;Kuramitsu S;Tobo T;Ogawa Y;Hu Q;Iguchi T;Kuroda Y;Ito S;Eguchi H;Sugimachi K;Saeki H;Oki E;Maehara Y;Suzuki A;Mimori K
YAP 1是一种通过去磷酸化和核转位而发挥作用的癌基因，其在细胞核内的积聚与胃癌的预后不良有关。我们以前确定伊维菌素，抗寄生虫药物，作为YAP 1抑制剂。在这里，我们的目的是澄清伊维菌素是否通过抑制YAP 1对GC具有抗肿瘤作用。首先，我们使用体外增殖试验和异种移植小鼠模型评估了伊维菌素对人GC细胞的抗增殖作用。进行YAP 1敲低测定以评估对伊维菌素的敏感性是否依赖于YAP 1表达。接下来，我们通过免疫印迹和YAP 1和下游基因CTGF的逆转录-定量聚合酶链反应，探索伊维菌素调节YAP 1表达或定位的机制。最后，使用三个独立的GC数据集检查YAP 1表达的临床意义。我们发现MKN 1 GC细胞对伊维菌素最敏感，而MKN 7细胞最耐药。在MKN 1异种移植物中，伊维菌素抑制肿瘤生长，YAP 1敲低降低了MKN 1细胞对伊维菌素的敏感性。伊维菌素抑制MKN 1细胞中YAP 1核表达和CTGF表达，但不抑制MKN 7细胞。此外，伊维菌素降低YAP 1 mRNA的表达，从而抑制YAP 1在MKN 1细胞核中的积累。在生存分析中，在三个独立的GC数据集中，低YAP 1 mRNA表达与较好的预后相关。总之，我们确定了伊维菌素作为一种潜在的抗肿瘤剂，并发现了一种有前途的新的治疗策略，通过阻断YAP 1的表达来抑制GC的进展。
Yes-associated protein 1 (YAP1) acts as an oncogene through dephosphorylation and nuclear translocation, and nuclear accumulation of YAP1 is associated with poor prognosis in gastric cancer (GC). We previously identified ivermectin, an antiparasitic drug, as a YAP1 inhibitor. Here, we aimed to clarify whether ivermectin had antitumor effects on GC through inhibition of YAP1. First, we evaluated the antiproliferative effects of ivermectin on human GC cells using in vitro proliferation assays and a xenograft mouse model. YAP1-knockdown assays were performed to assess whether the sensitivity to ivermectin depended on YAP1 expression. Next, we explored the mechanism through which ivermectin regulated YAP1 expression or localization by immunoblotting and reverse transcription-quantitative polymerase chain reaction for YAP1 and the downstream gene CTGF. Finally, the clinical significance of YAP1 expression was examined using three independent GC datasets. We found that MKN1 GC cells were most sensitive to ivermectin, whereas MKN7 cells were most resistant. In MKN1 xenografts, ivermectin suppressed tumor growth, and the sensitivity of MKN1 cells to ivermectin was decreased by YAP1 knockdown. Ivermectin inhibited YAP1 nuclear expression and CTGF expression in MKN1 cells but not MKN7 cells. Moreover, ivermectin decreased YAP1 mRNA expression, thereby inhibiting nuclear accumulation of YAP1 in MKN1 cells. In survival analysis, low YAP1 mRNA expression was associated with a better prognosis in three independent GC datasets. In conclusion, we identified ivermectin as a potential antitumor agent and found a promising novel therapeutic strategy for inhibition of GC progression by blocking YAP1 expression.
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癌基因 YAP1 与结直肠癌患者的不良预后和西妥昔单抗耐药性显着相关。
DOI：
10.1158/1078-0432.ccr-14-1374
发表时间：
2015-01-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Lee KW;Lee SS;Kim SB;Sohn BH;Lee HS;Jang HJ;Park YY;Kopetz S;Kim SS;Oh SC;Lee JS
通讯作者：
Lee JS
影响因子：
10.5
作者：
Zhao, Bin;Li, Li;Guan, Kun-Liang
通讯作者：
Guan, Kun-Liang
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影响因子：
13.3
作者：
Liu, Rui;Li, Jingyi;Wei, Yuquan
通讯作者：
Wei, Yuquan
影响因子：
37.3
作者：
Dueñas-González A;García-López P;Herrera LA;Medina-Franco JL;González-Fierro A;Candelaria M
通讯作者：
Candelaria M
影响因子：
11.4
作者：
Kanai, F;Marignani, PA;Yaffe, MB
通讯作者：
Yaffe, MB