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

miR-122 在胰腺癌中的抗肿瘤作用评估

• 批准号: 10437418
• 负责人: RAJGOPAL GOVINDARAJAN
• 金额: $ 7.88万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437418
• 关键词: Address; Attenuated; Biochemical; Breast; Caring; Cell Line; Cessation of life; Chemoresistance; Combined Modality Therapy; Complex; Data; Development; Divalent Cations; Down-Regulation; Drug resistance; Epigenetic Process; Epithelial; Evaluation; Exhibits; Extracellular Matrix; FOXP2 gene; Future; Gallbladder; Genes; Genetic; Genetic Transcription; Goals; Human; In Vitro; Intercellular Junctions; KPC model; KRASG12D; Knockout Mice; Laboratories; Liver; Lung; Malignant Neoplasms; Malignant neoplasm of pancreas; Mass Spectrum Analysis; Mesenchymal; Messenger RNA; Metabolic; MicroRNAs; Molecular; Mus; Neoplasm Metastasis; Outcome; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patient-Focused Outcomes; Persons; Pharmacology; Process; Property; Public Health; Publishing; RNA Interference; Regimen; Regulation; Research; Role; Signal Transduction; Solid Neoplasm; TP53 gene; Testing; Therapeutic; Tissues; Transgenic Organisms; Translations; Treatment Protocols; Treatment outcome; Tumor Biology; Tumor Suppressor Proteins; Tumorigenicity; Work; anticancer research; antitumor effect; base; epigenetic silencing; histone methylation; histone modification; improved; metabolomics; mouse model; mutant mouse model; novel; nucleoside analog; overexpression; pancreatic cancer model; pancreatic cancer patients; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; pancreatic tumorigenesis; therapy outcome; transcription factor; transcriptome sequencing; transcriptomics; transdifferentiation; translational applications; translational impact; tumor; tumor growth; tumor initiation; tumorigenic

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.

项目总结 MicroRNAs(MiRs)在肿瘤生物学和耐药性中的基础作用日益受到重视。 被认可了。本应用的目的是研究miR-122的肿瘤抑制作用，miR-122是一种富肝药。 胰腺癌中的MIR。我们发表的研究表明，表观遗传学的重新编程 胰腺癌中沉默的miRs可以抑制致瘤性和上皮-间充质转化(EMT)。 诱导的化疗耐药。在我们的初步研究中，我们发现在胰腺中沉默的miRs中 导管腺癌(PDAC)，miR-122显示出优越的抑制致瘤性和PDAC-122的能力。 体外联合EMT。我们在这一应用中的假设是miR-122是PDAC中的肿瘤抑制因子，并且 在转基因小鼠模型中miR-122功能的丧失或获得将产生重大影响 关于胰腺肿瘤的致瘤性和化疗耐药性。在目标1中，我们将研究miR-122在小鼠体内的作用 胰腺肿瘤的发生。这一目标得到了我们初步研究的支持，该研究表明miR-122 人PDAC组织中表达下调，miR-122具有抗肿瘤作用 人PDAC细胞系、原位和同基因小鼠PDAC模型。通过使用以下工具评估小鼠 全局和胰腺特异性缺失miR-122并通过转基因恢复miR-122在小鼠 KRAS-P53突变小鼠胰腺癌模型(KPC)，我们将研究miR-122对小鼠胰腺癌的影响。 小鼠PDAC的发生和发展。在目标2中，我们将研究miR-122的作用机制 抑制胰腺癌的EMT。由于EMT增强了耐药性，而miR-122抑制了前EMT 信号，我们将研究miR-122在胰腺癌EMT驱动的基因和通路中的作用；这 我们的初步研究支持这一方法，预测miR-122抑制假定的 通过RNA干扰获得EMT基因SLC39A9和FoxP2。使用生化方法和转录学 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 MiR-122调控的PDAC中EMT过程的代谢和转录景观。成功者 这两个目标的完成将为miR-122如何控制致瘤性提供令人信服的证据 胰腺癌的EMT可塑性。因此，这些研究将在胰腺癌方面开辟新的天地。 研究并可能对改善患者的治疗结果产生翻译影响。