Role of IL-6/STAT3 Signaling in the Neoplastic Progression of Barrett's Esophagus

IL-6/STAT3 信号转导在 Barrett 食管肿瘤进展中的作用

• 批准号: 8696814
• 负责人: RHONDA F SOUZA
• 金额: --
• 依托单位: VA NORTH TEXAS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696814
• 关键词: Address; Adenocarcinoma; Animal Model; Apoptosis; Attention; Automobile Driving; Barrett Esophagus; Barrett' s Adenocarcinoma; Benign; Biological Models; Biopsy Specimen; Blood Vessels; Cancerous; Carcinogenesis Mechanism; Cell Cycle; Cell Line; Cell Proliferation; Cell Survival; Cells; Chronic; Clinical; Colon; Colorectal Cancer; Contact Inhibition; Cytokine Inducible SH2-Containing Protein; Data; Development; Diagnosis; Disease; Epithelial; Epithelial Cells; Esophageal; Esophageal Adenocarcinoma; Esophageal Diseases; Event; Exhibits; Frequencies; Funding; Gastroesophageal reflux disease; Genetic; Growth; Human; Incidence; Inflammation; Inflammatory; Injury; Interleukin-6; Invaded; Longevity; Longitudinal Studies; MAPK3 gene; Malignant - descriptor; Malignant Neoplasms; Messenger RNA; Metaplasia; Metaplastic Cell; Molecular; Molecular Abnormality; Mutation; Neoplasm Metastasis; Neoplasms; Neoplastic Cell Transformation; Non-Malignant; Normal Cell; Oncogenic; Organ; PIAS3 Gene; PTPN11 gene; Pathway interactions; Patients; Peptic Esophagitis; Phenotype; Physiological; Physiology; Play; Population; Premalignant Cell; Prevention; Prevention strategy; Process; Protein Secretion; Protein Tyrosine Phosphatase; Proteins; Regulatory Pathway; Research; Risk Factors; Role; STAT3 gene; Series; Signal Pathway; Signal Transduction; Staging; Structure; T-Lymphocyte; Telomerase; Time; Tissues; Transformed Cell Line; Tumorigenicity; Veterans; abstracting; angiogenesis; base; cancer cell; carcinogenesis; cell growth; cell transformation; colon carcinogenesis; cytokine; in vitro Model; in vivo; migration; mutant; neoplastic; neoplastic cell; prevent; promoter; protein inhibitors of activated STAT; species difference; therapy development; transcription factor; treatment strategy; tumor; tumor microenvironment; tumor progression

DESCRIPTION (provided by applicant): Project Summary/Abstract Gastroesophageal reflux disease and Barrett's esophagus, common disorders in Veteran patients, are the major risk factors for esophageal adenocarcinoma, a lethal tumor whose frequency has increased more than six-fold in the past few decades. The development of therapies to prevent or cure this lethal tumor has been hampered by limited understanding of the molecular events underlying the neoplastic progression of Barrett's metaplasia. During carcinogenesis in Barrett's esophagus, genetic alterations accumulate that enable the cells to provide their own growth signals, avoid growth inhibitory signals, resist apoptosis, replicate without limit, synthesize new blood vessels, invade adjacent organs and metastasize. These physiologic "hallmarks" of cancer, which were described by Hanahan and Weinberg in 2000, can be acquired by normal cells through disruptions in surprisingly few key growth regulatory pathways. Recently, cancer-related inflammation has been proposed as another physiologic hallmark of cancer that can be established through two pathways: 1) an extrinsic pathway in which disorders such as reflux esophagitis cause tissue inflammation that contributes to carcinogenesis, and 2) an intrinsic pathway in which the precancerous cells acquire genetic abnormalities that produce an inflammatory tumor microenvironment. Both pathways can converge on certain key downstream targets such as IL-6, a potent inflammatory cytokine that is known to promote cellular growth, and STAT3, a transcription factor that has a key role in IL-6 signal transduction. Chronic esophageal inflammation due to reflux esophagitis is widely regarded as the extrinsic pathway for promoting carcinogenesis in Barrett's esophagus, but little attention has been directed at the intrinsic inflammatory pathway and the role of IL-6/STAT3 signaling in the malignant progression of Barrett's metaplasia. Studies on the early molecular events that transform Barrett's metaplasia into adenocarcinoma have been hampered by the lack of appropriate model systems. During our last cycle of Merit Review funding, we addressed this deficiency by establishing cultures of non- neoplastic Barrett's epithelial (BAR-T) cells that we immortalized through the forced expression of telomerase. Using a combination of p53 knockdown and forced expression of oncogenic H- RasG12V, we have induced the malignant transformation of those BAR-T cells and, in the process, established a series of Barrett's epithelial cell lines with well defined genetic alterations representing various stages in the transition from benign Barrett's metaplasia to cancer. Our preliminary data demonstrate that the transformed Barrett's cells express IL-6 mRNA and exhibit a significant increase in IL-6 protein secretion. Moreover, we have found that IL-6 signaling causes an increase in phospho-STAT3 levels in the transformed cells, and that activation of the IL-6/STAT3 pathway endows the cells with the ability to resist apoptosis and to secrete angiogenesis-promoting factors. We propose to use our unique series of Barrett's epithelial cell lines to explore the role of the IL-6/STAT3 pathway in driving the malignant transformation of Barrett's esophagus. We hypothesize that activation of the IL-6/STAT3 signaling pathway plays a key role in driving the neoplastic transformation of Barrett's metaplasia. Based on our preliminary data, the objectives of our study are to delineate the mechanism(s) whereby p53 inactivation and Ras activation result in activation of the IL-6/STAT3 signaling pathway in Barrett's epithelial cells, to determine the effects of activation and inactivation of the IL-6/STAT3 pathway on the level of neoplastic transformation in Barrett's cell lines, and to correlate p53 inactivation and Ras pathway activation with the activation of the IL-6/STAT3 pathway during the neoplastic progression of Barrett's esophagus in vivo using biopsy specimens from patients with non- dysplastic Barrett's esophagus, dysplastic Barrett's esophagus (low-grade and high-grade), and Barrett's adenocarcinoma.

描述（由申请人提供）： 项目摘要/摘要胃食管反流疾病和Barrett的食管（在退伍军人患者中的常见疾病）是食管腺癌的主要危险因素，食管腺癌是一种致命的肿瘤，其频率在过去几十年中的频率增加了六倍以上。对预防或治愈这种致命肿瘤的疗法的发展受到了对巴雷特化学肿瘤进展为基础的分子事件的有限理解。 在巴雷特食管的癌变期间，遗传改变积累，使细胞能够提供自身的生长信号，避免生长抑制信号，抵抗凋亡，无限制复制，合成新的血管，侵入相邻的器官并转移。这些癌症的生理“标志”是由哈纳汉（Hanahan）和温伯格（Weinberg）在2000年描述的，可以通过正常细胞可以通过令人惊讶的关键生长调节途径的干扰来获取。最近，已经提出了与癌症相关的炎症为癌症的另一种生理标志，可以通过两种途径建立：1）一种外部途径，其中一种疾病（例如反流性食管炎）会导致组织炎症，从而有助于癌变，以及2）一种内在的途径，在该途径中会产生percancer骨遗传学症状的脑膜化症状。这两种途径均可在某些键下游靶标上收敛，例如IL-6，这是一种有效的炎症细胞因子，已知可以促进细胞生长，而STAT3（STAT3）是在IL-6信号转导中具有关键作用的转录因子。反流食管炎引起的慢性食管炎症被广泛认为是促进巴雷特食管中癌变的外部途径，但很少关注炎症途径，并且对IL-6/Stat3信号在Barrett Metaplasia的恶性进展中的作用和IL-6/Stat3信号的作用。 缺乏适当的模型系统，对将Barrett的化生变成腺癌的早期分子事件的研究受到了阻碍。在我们的最后一个值得审查资金周期中，我们通过建立非肿瘤性Barrett上皮（BAR-T）细胞的培养物来解决这种缺陷，我们通过端粒酶的强制表达使我们永生化。利用p53敲低和强迫表达致癌性H-RASG12V的强迫表达，我们诱导了这些BAR-T细胞的恶性转化，在此过程中，我们建立了一系列Barrett的Barrett上皮细胞系，具有明确定义的遗传变化，这些遗传变化是从良性Barrett Barrett Metaplasia转变为癌症的各个阶段的。我们的初步数据表明，转化的Barrett细胞表达IL-6 mRNA，并显示IL-6蛋白分泌的显着增加。此外，我们发现IL-6信号传导导致转化细胞中磷酸-STAT3水平的增加，并且IL-6/STAT3途径的激活使细胞具有抵抗凋亡和分泌血管生成促进因子的能力。我们建议使用我们独特的Barrett上皮细胞系系列，以探索IL-6/STAT3途径在推动Barrett食管的恶性转化中的作用。 我们假设IL-6/STAT3信号通路的激活在推动Barrett Metaplasia的肿瘤转化中起关键作用。基于我们的初步数据，我们的研究目标是描述p53灭活和RAS激活的机制，导致Barrett上皮细胞中IL-6/STAT3信号通路的激活，以确定IL-6/STAT3 pARTOR的影响IL-6/STAT3 PARTOR的影响，以确定IL-6/STAT3 PATH的影响。在Barrett的食管肿瘤进展过程中，使用非塑性障碍性Barrett的食管食管，具有变形障碍性的Barrett的食管（低层和高层）和Barrett的EneNocarcin的患者，使用活检标本（低塑性性Barrett的食管患者），使用活检标本，使用活检标本（低塑性疾病）和RAS途径激活IL-6/STAT3途径在体内的肿瘤进展过程中激活。