Upregulation of miR-181c contributes to chemoresistance in pancreatic cancer by inactivating the Hippo signaling pathway.
Upregulation of miR-181c contributes to chemoresistance in pancreatic cancer by inactivating the Hippo signaling pathway.
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DOI：
10.18632/oncotarget.6298
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发表时间：
2015-12-29
期刊：
影响因子：
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通讯作者：
Jiang J
中科院分区：
文献类型：
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作者：
Chen M;Wang M;Xu S;Guo X;Jiang J
Hippo信号通路在失调时在调节组织稳态、器官大小、肿瘤发生和癌症化学抗性中起关键作用。在生理学上，由哺乳动物STE 20样蛋白激酶1/2（MST 1/2）和大肿瘤抑制因子1/2（LATS 1/2）以及衔接蛋白萨尔瓦多同源物1（SAV 1）和MOB激酶激活因子1（MOB 1）组成的Hippo核心激酶盒，严格限制同源癌蛋白Yes相关蛋白（雅普）和PDZ结合基序转录辅激活因子（TAZ）的活性低水平。然而，Hippo激酶盒核心组分如何同时被抑制，从而在癌症中表现出组成性失活的Hippo信号传导和活化的雅普/TAZ仍然令人困惑。在此，我们报道了miR-181 c直接抑制人胰腺癌细胞中MST 1、LATS 2、MOB 1和SAV 1的表达。miR-181 c的过表达诱导雅普/TAZ的过度活化，并增强Hippo信号传导下游基因CTGF、BIRC 5和BLC 2L 1的表达，导致胰腺癌细胞存活和体外和体内的化学抗性。重要的是，高miR-181 c水平与胰腺癌样本中的Hippo信号转导失活显著相关，并预测患者总体生存率较差。这些发现为癌症中的Hippo信号转导失活提供了一种新的机制，表明miR-181 c不仅在胰腺癌的进展中具有潜在的关键作用，而且可能代表新的治疗靶点和预后标志物。
The Hippo signaling pathway plays a crucial role in regulating tissue homeostasis, organ size, tumorigenesis and cancer chemoresistance when deregulated. Physiologically, the Hippo core kinase cassette that consists of mamma-lian STE20-like protein kinase 1/2 (MST1/2), and large tumour suppressor 1/2 (LATS1/2), together with the adaptor proteins Salvador homologue 1 (SAV1) and MOB kinase activator 1 (MOB1), tightly restricts the activities of homologous oncoproteins Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) to low levels. However, how the Hippo kinase cassette core components are simultaneously inhibited, to exhibit constitutively inactivated Hippo signaling and activated YAP/TAZ in cancer remains puzzling. Herein, we reported that miR-181c directly repressed MST1, LATS2, MOB1 and SAV1 expression in human pancreatic cancer cells. Overexpression of miR-181c induced hyperactivation of the YAP/TAZ and enhanced expression of the Hippo signaling downstream genes CTGF, BIRC5 and BLC2L1, leading to pancreatic cancer cell survival and chemoresistance in vitro and in vivo. Importantly, high miR-181c levels were significantly correlated with Hippo signaling inactivation in pancreatic cancer samples, and predicted a poor patient overall survival. These findings provide a novel mechanism for Hippo signaling inactivation in cancer, indicating not only a potentially pivotal role for miR-181c in the progression of pancreatic cancer, but also may represent a new therapeutic target and prognostic marker.