YAP-associated chromosomal instability and cholangiocarcinoma in mice.
YAP-associated chromosomal instability and cholangiocarcinoma in mice.
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DOI：
10.18632/oncotarget.23638
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发表时间：
2018-01-19
期刊：
影响因子：
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通讯作者：
Gores GJ
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作者：
Rizvi S;Fischbach SR;Bronk SF;Hirsova P;Krishnan A;Dhanasekaran R;Smadbeck JB;Smoot RL;Vasmatzis G;Gores GJ
Hippo通路信号转导失调与下游效应细胞相关蛋白（雅普）的异常激活相关，YAP是胆管癌（CCA）中新出现的关键致癌介质。在我们之前的工作中，我们已经证明了雅普沿着Akt作为允许因子的胆汁转导在小鼠中诱导CCA。为了进一步阐明与YAP相关的胆管肿瘤发生的机制，我们从YAP驱动的小鼠CCA模型中建立了7种恶性小鼠细胞系。这些细胞表达CCA标志物SRY（性别决定区Y）-框9（SOX 9）、细胞角蛋白（CK）-7和19，但缺乏肝细胞核因子4 α和α-平滑肌肌动蛋白（分别为肝细胞癌和癌症相关成纤维细胞的标志物）。值得注意的是，鼠CCA细胞可以容易地植入小鼠肝脏中，从而形成原位肿瘤。在这种独特的同基因原位小鼠模型中，肿瘤表现出类似于人CCA的组织病理学特征。我们分析了YAP相关的亲本CCA肿瘤结节的转录组数据，并确定了与染色体不稳定性相关的基因表达模式，称为CIN 25。类似地，鼠CCA细胞的配对测序揭示了染色体错误分离，几个完整染色体的获得和丢失证明了非整倍性。在CIN 25基因中，叉头框M1（Foxm 1），一种关键的细胞周期调节因子，是最显著上调的CIN 25基因产物。因此，小干扰RNA（siRNA）介导的雅普沉默以及用硫链丝菌素抑制FOXM 1诱导CCA细胞死亡。这些临床前数据暗示了YAP介导的染色体不稳定性在胆管癌中的作用，并表明FOXM 1抑制作为CCA的治疗靶点。
Deregulated Hippo pathway signaling is associated with aberrant activation of the downstream effector yes-associated protein (YAP), an emerging key oncogenic mediator in cholangiocarcinoma (CCA). In our prior work, we have demonstrated that biliary transduction of YAP along with Akt as a permissive factor induces CCA in mice. To further delineate the mechanisms associated with YAP-associated biliary oncogenesis, we have established seven malignant murine cell lines from our YAP-driven murine CCA model. These cells express the CCA markers SRY (Sex Determining Region Y)-Box 9 (SOX9), cytokeratin (CK)-7 and 19 but lack hepatocyte nuclear factor 4 alpha and alpha-smooth muscle actin, markers of hepatocellular carcinoma and cancer-associated fibroblasts, respectively. Notably, the murine CCA cells can be readily implanted into mouse livers with resultant orthotopic tumor formation. In this unique syngeneic orthotopic murine model, tumors exhibit histopathologic features resembling human CCA. We analyzed transcriptome data from YAP-associated parent CCA tumor nodules and identified a gene expression pattern associated with chromosomal instability, known as CIN25. Similarly, mate-pair sequencing of the murine CCA cells revealed chromosomal missegregation with gains and losses of several whole chromosomes demonstrating aneuploidy. Of the CIN25 genes, forkhead box M1 (Foxm1), a key cell cycle regulator, was the most significantly upregulated CIN25 gene product. Accordingly, small interfering RNA (siRNA)-mediated silencing of YAP as well as FOXM1 inhibition with thiostrepton induced CCA cell death. These preclinical data imply a role for YAP-mediated chromosomal instability in cholangiocarcinoma, and suggest FOXM1 inhibition as a therapeutic target for CCA.