Expression of DRD2 Is Increased in Human Pancreatic Ductal Adenocarcinoma and Inhibitors Slow Tumor Growth in Mice
Expression of DRD2 Is Increased in Human Pancreatic Ductal Adenocarcinoma and Inhibitors Slow Tumor Growth in Mice
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DOI：
10.1053/j.gastro.2016.08.040
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发表时间：
2016-12-01
期刊：
影响因子：
29.4
通讯作者：
Hoheisel, Joerg D.
中科院分区：
文献类型：
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作者：
Jandaghi, Pouria;Najafabadi, Hamed S.;Hoheisel, Joerg D.
背景与目的：胰腺导管腺癌是胰腺癌中最常见的一种，其发病率和死亡率几乎相同，因此需要更好的治疗方法。我们研究了PDAC的基因表达谱和表达改变的基因的功能，以确定新的治疗靶点。方法：应用基因芯片技术分析195例胰腺癌组织和41例非肿瘤胰腺组织的基因表达谱。我们对PDAC转录组进行了广泛的分析，通过将异常表达的基因编码的蛋白质相互作用网络叠加到与PDAC发育相关的信号通路上，以确定在肿瘤进展过程中可能改变这些通路调节的因素。我们使用一组独立的152个样本(40个非肿瘤胰腺组织、63个PDAC切片和49个慢性胰腺炎样本)进行组织微阵列分析以验证候选蛋白表达的变化。我们使用RNA干扰或药物抑制剂在胰腺癌细胞系中验证了候选分子的功能相关性，并对小鼠的异种移植瘤进行了分析。结果：在对38,276个人类基因和位点的分析中，我们发现与非肿瘤胰腺组织相比，PDAC中有1676个基因显著上调，1166个基因显著下调。在PDAC中，一个上调并与多个信号通路相关的基因是G蛋白亚基αi2，它以前没有与PDAC相关。G蛋白亚基αi2介导多巴胺受体D2(DRD2)对环磷酸腺苷信号的影响；PDAC组织中DRD2信使RNA略有增加，但显著增加。在组织芯片分析中，与非肿瘤组织相比，PDAC中DRD2蛋白的水平显著增加。RNA干扰下调DRD2或用药物拮抗剂(吡莫齐特和氟哌啶醇)抑制胰腺癌细胞的增殖，诱导内质网应激和细胞凋亡，并减少细胞迁移。RNA干扰敲除胰腺肿瘤细胞中的DRD2减少了小鼠异种移植瘤的生长，对原位异种移植瘤小鼠给予DRD2抑制剂氟哌啶醇可以减少最终的肿瘤大小和转移。结论：在PDAC样本的基因表达谱分析中，我们发现DRD2信号通路被激活。抑制胰腺癌细胞中的DRD2减少了小鼠移植瘤的增殖和迁移，并减缓了肿瘤的生长。常规用于治疗精神分裂症的DRD2拮抗剂可能会在胰腺癌患者身上进行测试。
BACKGROUND & AIMS: Incidence of and mortality from pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, are almost equivalent, so better treatments are needed. We studied gene expression profiles of PDACs and the functions of genes with altered expression to identify new therapeutic targets. METHODS: We performed microarray analysis to analyze gene expression profiles of 195 PDAC and 41 non-tumor pancreatic tissue samples. We undertook an extensive analysis of the PDAC transcriptome by superimposing interaction networks of proteins encoded by aberrantly expressed genes over signaling pathways associated with PDAC development to identify factors that might alter regulation of these pathways during tumor progression. We performed tissue microarray analysis to verify changes in expression of candidate protein using an independent set of 152 samples (40 nontumor pancreatic tissues, 63 PDAC sections, and 49 chronic pancreatitis samples). We validated the functional relevance of the candidate molecule using RNA interference or pharmacologic inhibitors in pancreatic cancer cell lines and analyses of xenograft tumors in mice. RESULTS: In an analysis of 38,276 human genes and loci, we identified 1676 genes that were significantly up-regulated and 1166 genes that were significantly down-regulated in PDAC compared with nontumor pancreatic tissues. One gene that was up-regulated and associated with multiple signaling pathways that are dysregulated in PDAC was G protein subunit alpha i2, which has not been previously associated with PDAC. G protein subunit alpha i2 mediates the effects of dopamine receptor D2 (DRD2) on cyclic adenosine monophosphate signaling; PDAC tissues had a slight but significant increase in DRD2 messenger RNA. Levels of DRD2 protein were substantially increased in PDACs, compared with non-tumor tissues, in tissue microarray analyses. RNA interference knockdown of DRD2 or inhibition with pharmacologic antagonists (pimozide and haloperidol) reduced proliferation of pancreatic cancer cells, induced endoplasmic reticulum stress and apoptosis, and reduced cell migration. RNA interference knockdown of DRD2 in pancreatic tumor cells reduced growth of xenograft tumors in mice, and administration of the DRD2 inhibitor haloperidol to mice with orthotopic xenograft tumors reduced final tumor size and metastasis. CONCLUSIONS: In gene expression profile analysis of PDAC samples, we found the DRD2 signaling pathway to be activated. Inhibition of DRD2 in pancreatic cancer cells reduced proliferation and migration, and slowed growth of xenograft tumors in mice. DRD2 antagonists routinely used for management of schizophrenia might be tested in patients with pancreatic cancer.