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Surgical Studies on the Role of MicroRNAs in Esophageal Cancer

MicroRNA 在食管癌中作用的外科研究

基本信息

批准号：
10364596
负责人：
James M Donahue
金额：
--
依托单位：
BIRMINGHAM VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10364596
关键词：
Aftercare Age Apoptosis Binding Biological Markers Biopsy Cancer cell line Cells Characteristics Chemotherapy and/or radiation Clinical Data Development Disease Down-Regulation Ectopic Expression Engineering Epithelial Epithelial Cells Esophagectomy Esophagus Evaluation Excision Gene Expression Goals Growth Healthcare Healthcare Systems Human Implant Incidence Individual MAP Kinase Kinase Kinase Malignant Neoplasms Malignant neoplasm of esophagus Messenger RNA Methods MicroRNAs Mission Modality Morbidity - disease rate Nude Mice Oncogenes Oncogenic Operative Surgical Procedures Outcome Pathogenesis Pathologic Patients Pattern Postoperative Care Problem Solving Prognostic Marker Regimen Role Sampling Small RNA Specimen Surgeon Surgical Management Survival Rate System Techniques Testing Therapeutic Translations Treatment Protocols Tumor Suppressor Proteins Untranslated RNA Work advanced disease alternative treatment base cancer cell cell type chemotherapy demographics diagnostic biomarker differential expression esophageal cancer patient esophageal carcinogenesis experience improved improved outcome in vivo male mortality new therapeutic target novel operation overexpression perioperative mortality predictive marker prognostic response surgery outcome survivin therapeutic miRNA therapeutic target treatment strategy tumor

项目摘要

Background: Despite significant reductions in the morbidity and mortality associated with esophagectomy, survival for patients with esophageal cancer remains dismal. In most patients, adjunctive therapies including chemotherapy and radiation are beneficial. In fact, patients who achieve a complete pathologic response (pCR) after treatment with chemotherapy and radiation followed by esophagectomy often experience greatly improved survival. Unfortunately, the percentage of patients who currently achieve a pCR is low. Improving survival for esophageal cancer patients following esophagectomy requires that we ascertain how to increase the number of patients who achieve a pCR. In other malignancies, microRNAs (miRs) have been found to serve as effective diagnostic, prognostic, and predictive biomarkers. In addition, based on their ability to function as oncogenes or tumor suppressors, miR-based therapeutic approaches are currently being investigated. The role of miRs in the pathogenesis and treatment of esophageal cancer has not been thoroughly evaluated. Objectives: The primary objective of this study is to identify new biomarkers and therapeutic targets based an analysis of miR expression and function in esophageal cancer cells. Preliminary Findings: Our preliminary studies indicate that a) miR-214-3p and miR-199a-5p are dramatically downregulated in esophageal cancer cell lines compared to esophageal epithelial cells, b) this expression pattern has been verified in initial human tumor samples, c) specific binding interactions have been identified between miR-214-3p and miR-199a-5p with the oncogenic targets survivin and mitogen activated protein kinase kinase kinase 11 (MAP3K11), respectively, d) ectopic expression of miR-214-3p and miR-199a-5p results in a marked decrease in the levels of survivin and MAP3K11 in esophageal cancer cells, and e) ectopic expression of miR-214-3p and miR-199a-5p results in important functional consequences; specifically, increased sensitivity to chemotherapy-induced apoptosis and decreased proliferation, respectively. Based on these exciting observations, we HYPOTHESIZE that downregulation of miR-214-3p and miR-199a-5p occurs frequently in esophageal cancer cells and can be exploited for prognostic, predictive, and therapeutic purposes. Methods: To test this hypothesis, we propose 3 specific aims. (1) To characterize expression of miR- 214-3p and miR-199a-5p in human esophageal cancer specimens and correlate expression with clinical outcomes. Pretreatment biopsies of both tumor and normal esophageal epithelium will be obtained from 50 patients for evaluation of miR-214-3p and miR-199a-5p expression and correlation with outcomes. (2) To identify novel targets of miR-214-3p and miR-199a-5p that contribute to the development and progression of esophageal cancer. We will utilize human esophageal cancer cell lines to identify new targets and functions of miR-214-3p and miR-199a-5p in esophageal cancer cells. (3) To determine the anti-tumor efficacy of miR-214-3p and miR-199a-5p overexpression in vivo. Human esophageal cancer cell lines will be engineered to stably express selected miR-214-3p or miR-199a-5p. These engineered cells will then be implanted in nude mice. Their growth characteristics and response to chemotherapy will be compared to wild-type cells. Status: This is a resubmission. Impact: The incidence of esophageal cancer continues to increase in the Untied Sates, especially in males over the age of 50. Based on these demographics, this disease represents a significant problem in the VA healthcare system. Improving outcomes for esophageal cancer patients will greatly enhance the ability of the VA to fulfill its healthcare mission.

背景：尽管食管切除术相关的发病率和死亡率显着降低，食管癌患者的生存率仍然很低。对于大多数患者，辅助治疗包括化疗和放疗是有益的。事实上，达到完全病理反应的患者 (pCR) 化疗和放疗后进行食管切除术通常会经历很大的困难提高生存率。不幸的是，目前达到 pCR 的患者比例很低。改善为了提高食管癌患者食管切除术后的生存率，我们需要确定如何提高食管癌患者的生存率。达到 pCR 的患者数量。在其他恶性肿瘤中，microRNA (miR) 已被发现作为有效的诊断、预后和预测生物标志物。另外，根据自己的能力作为癌基因或肿瘤抑制基因，基于 miR 的治疗方法目前正在研究中调查了。 miRs在食管癌发病机制和治疗中的作用尚未明确彻底评估。目的：本研究的主要目的是根据现有技术确定新的生物标志物和治疗靶点。食管癌细胞中miR表达及功能分析初步发现：我们的初步研究表明 a) miR-214-3p 和 miR-199a-5p 显着与食管上皮细胞相比，食管癌细胞系中表达下调，b) 这种表达模式已在初始人类肿瘤样本中得到验证，c) 特异性结合相互作用已被识别 miR-214-3p 和 miR-199a-5p 之间与致癌靶点生存素和丝裂原激活蛋白激酶激酶激酶 11 (MAP3K11)，分别 d) miR-214-3p 和 miR-199a-5p 的异位表达导致食管癌细胞中生存素和 MAP3K11 水平显着下降，以及 e) 异位 miR-214-3p 和 miR-199a-5p 的表达会产生重要的功能后果；具体来说，分别增加对化疗诱导的细胞凋亡的敏感性和减少的增殖。基于这些令人兴奋的观察结果，我们假设 miR-214-3p 和 miR-199a-5p 发生下调经常出现在食管癌细胞中，可用于预后、预测和治疗目的。方法：为了检验这一假设，我们提出了 3 个具体目标。 (1) 表征 miR-的表达人食管癌标本中的 214-3p 和 miR-199a-5p 及其表达与临床的相关性结果。肿瘤和正常食管上皮的预处理活检将从 50 个样本中获得患者评估 miR-214-3p 和 miR-199a-5p 表达及其与结果的相关性。 (2) 至确定 miR-214-3p 和 miR-199a-5p 的新靶点，这些靶点有助于疾病的发展和进展食道癌。我们将利用人食管癌细胞系来识别食管癌细胞的新靶点和功能食管癌细胞中的 miR-214-3p 和 miR-199a-5p。 (3) 抗肿瘤功效的测定 miR-214-3p 和 miR-199a-5p 体内过表达。人类食管癌细胞系将被改造稳定表达选定的miR-214-3p或miR-199a-5p。然后这些工程细胞将被植入裸体内老鼠。它们的生长特征和对化疗的反应将与野生型细胞进行比较。状态：这是重新提交。影响：独立国家的食道癌发病率持续上升，尤其是男性 50 岁以上。根据这些人口统计数据，这种疾病是退伍军人事务部的一个重大问题医疗保健系统。改善食管癌患者的治疗效果将大大增强食管癌患者的治疗能力 VA 履行其医疗保健使命。