Evaluation of the antitumorigenic roles of miR-122 in pancreatic cancer

项目摘要 microRNA（miRs）在肿瘤生物学和耐药性中的基础作用越来越受到关注。 认可.本申请的目的是研究miR-122的肿瘤抑制作用， 胰腺癌中的miR。我们发表的研究表明，表观遗传重编程的 胰腺癌中沉默的miR可以抑制致瘤性和上皮-间质转化（EMT）。 诱导耐药性。在我们的初步研究中，我们发现在胰腺癌中沉默的miR中， 在乳腺导管腺癌（PDAC）中，miR-122在抑制致瘤性和PDAC-1方面表现出上级效力。 体外相关EMT。我们在本申请中的假设是miR-122是PDAC中的肿瘤抑制因子， 在基因修饰的小鼠模型中，miR-122功能的丧失或获得将对小鼠产生显著影响。 对胰腺肿瘤发生和化疗耐药性的影响。目的一：研究miR-122在小鼠脑内的作用， 胰腺肿瘤发生我们的初步研究表明，miR-122 人PDAC组织中的表达下调，并且miR-122发挥抗肿瘤作用 人PDAC细胞系以及PDAC的原位和同基因小鼠模型中。通过评估小鼠， miR-122的整体和胰腺特异性缺失，以及通过转基因恢复miR-122在胰腺癌中的表达， Kras-p53突变小鼠胰腺癌模型（KPC），我们将研究miR-122对胰腺癌发生的影响。 小鼠PDAC的起始和进展。在目标2中，我们将研究miR-122 抑制胰腺癌的EMT由于EMT增强耐药性，而miR-122抑制pro-EMT， 信号，我们将研究miR-122对胰腺癌中EMT驱动基因和途径的影响; 我们的初步研究预测miR-122抑制了推定的 EMT基因SLC 39 A9和FoxP 2通过RNA干扰。使用生化方法和转录组学 和代谢组学研究，我们将揭示miR-122及其mRNA靶点在EMT中的作用，并确定 PDAC中miR-122调节的EMT过程的代谢和转录组学景观。成功 这两个目标的实现将为miR-122如何控制致瘤性提供令人信服的证据 和胰腺癌中EMT的可塑性。因此，这些研究将为胰腺癌的治疗开辟新的天地。 研究，并可能对改善患者的治疗结果产生转化影响。

PROJECT SUMMARY The fundamental roles of microRNAs (miRs) in tumor biology and drug resistance are increasingly being recognized. The objective of this application is to study the tumor suppressor role of miR-122, a liver-enriched miR, in pancreatic cancer. Our published research demonstrates that the epigenetic reprogramming of silenced miRs in pancreatic cancer can inhibit tumorigenicity and epithelial-mesenchymal transition (EMT)- induced chemoresistance. In our preliminary studies, we found that among the miRs silenced in pancreatic ductal adenocarcinoma (PDAC), miR-122 exhibits superior potency in suppressing tumorigenicity and PDAC- associated EMT in vitro. Our hypothesis in this application is that miR-122 is a tumor suppressor in PDAC and that the loss or gain of miR-122 function in genetically modified mouse models would have significant effects on pancreatic tumorigenicity and chemoresistance. In Aim 1, we will study the role of miR-122 in mouse pancreatic tumorigenesis. This aim is supported by our preliminary studies demonstrating that miR-122 expression is downregulated in human PDAC tissues and that miR-122 exerts anti-tumorigenic effects in human PDAC cell lines and in orthotopic and syngeneic mouse models of PDAC. By evaluating mice with global and pancreas-specific deletion of miR-122 and by transgenically restoring miR-122 expression in a Kras-p53 mutant mouse model of pancreatic cancer (KPC), we will investigate the impact of miR-122 on the initiation and progression of mouse PDAC. In Aim 2, we will investigate the mechanism by which miR-122 inhibits EMT in pancreatic cancer. Since EMT enhances drug resistance and miR-122 inhibits pro-EMT signals, we will study the effect of miR-122 on EMT-driven genes and pathways in pancreatic cancer; this approach is supported by our preliminary studies predicting that miR-122 inhibits the expression of the putative EMT genes SLC39A9 and FoxP2 through RNA interference. Using biochemical approaches and transcriptomic and metabolomic studies, we will reveal the role of miR-122 and its mRNA targets in EMT and also determine the metabolic and transcriptomic landscapes of miR-122-regulated EMT processes in PDAC. The successful completion of both of these aims would provide convincing evidence of how miR-122 controls tumorigenicity and EMT plasticity in pancreatic cancer. Thus, these studies will break new ground in pancreatic cancer research and may have a translational impact on improving therapeutic outcomes for patients.