The role of the tumor suppressor RhoB in pulmonary aging and lung tumorigenesis

抑癌基因RhoB在肺衰老和肺肿瘤发生中的作用

基本信息

批准号：
9043835
负责人：
CHRISTINE L. HANN
金额：
$ 17.62万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9043835
关键词：
A/J Mouse Affect Age Age-Years Aging Alleles Apoptosis Attenuated Biological Biological Models Biological Preservation Bronchoalveolar Lavage C57BL/6 Mouse CDKN2A gene Cancer Etiology Cells Cessation of life Chronic Clinical DNA Damage DNA Repair Data Development Dominant-Negative Mutation Double Strand Break Repair Elderly Epithelial Cells Event Exposure to FRAP1 gene Gene Expression Profiling Genomic Instability Genotoxic Stress HDAC1 gene Health Human Incidence Inflammation Inflammatory KRAS2 gene Knock-out Lesion Link Longevity Lung Lung Neoplasms Maintenance Malignant Neoplasms Malignant neoplasm of lung Mediating Molecular Mus Mutate Mutation NF-kappa B Oncogene Activation Oncogenic PI3K/AKT PTEN gene Pathway interactions Play Population Premalignant Process Protein Dephosphorylation Protein Isoforms Protein Phosphatase 2A Regulatory Subunit PR53 Reporter Respiratory physiology Role Signal Pathway Signal Repression Signal Transduction Smoker Structure of parenchyma of lung System TP53 gene Testing Tissues Tobacco Tobacco-Associated Carcinogen Tumor Suppression Tumor Suppressor Proteins age related aged cancer diagnosis carcinogenesis cell injury cell transformation cigarette smoke-induced cigarette smoking cytokine environmental tobacco smoke exposure histone modification human old age (65+)innovation insight lung cancer prevention lung tumorigenesis metaplastic cell transformation mouse model mutant overexpression prevent promoter reconstitution rho GTP-Binding Proteins rhoB GTP-Binding Protein transcription factor tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer-related death worldwide, and commonly occurs in smokers. Most lung cancers are diagnosed when people are older than 65 years of age. Although the process by which aging promotes cancer is far from clear, evidence suggests that the accumulation of mutations and increased inflammation in aged tissues drive cancer development, which is promoted by activation of signaling pathways such as the PI3K/AKT/mTOR pathway. Our previous studies demonstrated that Akt activation is induced by tobacco components and is important for lung cancer formation, maintenance, and chemoresistance. Using microarray profiling, we showed that the tumor suppressor RhoB is down regulated in bronchial epithelial cells as they progress from immortalization to full transformation. RhoB is suppressed by Akt-mediated oncogenic inhibition of FoxO3A, a transcription factor at the interface between longevity and tumor suppression. In a feedforward manner, RhoB also suppresses Akt activity in human bronchial epithelial cells. RhoB loss is a frequent event in lung cancer, which could contribute to Akt activation during carcinogenesis. In addition, the RhoB promoter is gradually silenced in lung tissue as mice age, and is epigenetically suppressed in human lung cancer. The gradual loss of RhoB might increase genome instability of airway epithelial cells, accelerate pulmonary aging, and make damaged cells more vulnerable to cancer progression, especially when exposed to cigarette smoke. We hypothesize that loss of RhoB lung promotes contributes to pulmonary aging and lung tumorigenesis. Our preliminary data demonstrates that RhoB protein is decreased in the lungs of A/J mice during aging and is further decreased by exposure to the tobacco carcinogen NNK that activates Akt. These results provide strong rationale to study the role of RhoB at the lung aging/cancer interface by testing the following specific aims. Specific Aim1 will investigate the role of RhoB on mouse lung aging and tumorigenesis. By comparing age-dependent changes of DNA damage and genomic instability in lung tissue, bronchoalveolar lavage cell composition and inflammatory cytokine profile, as well as tumor multiplicity and size between the age-matched, wildtype and RhoB knockout LSL K-ras G12D C57BL/6 mice without or with mutant K-ras activation, we will be able to directly assess the biological consequences of RhoB loss during pulmonary aging and lung tumorigenesis. Specific Aim 2 will determine if reconstitution of RhoB in aged mice prevents lung tumorigenesis. By genetically restoring RhoB expression in aged LSL K-ras G12D C57BL/6 or cigarette smoke-exposed A/J lung tumor mouse models before tumor formation, we will be able to test whether reconstitution of RhoB could prevent or attenuate lung tumorigenesis in aged mice. These innovative studies will provide mechanistic insight into pulmonary aging and the development of lung cancer. Moreover, they have potential clinical implications for preservation of lung function and prevention of lung cancer in elderly populations through reactivation of RhoB.

描述（由适用提供）：肺癌是全球与癌症相关死亡的主要原因，通常发生在吸烟者中。大多数肺癌在年龄大于65岁的人时被诊断出来。尽管促进癌症的过程远非清晰，但有证据表明，衰老组织中突变和感染的增加驱动癌症发展，这是通过信号传导途径（例如PI3K/AKT/MTOR途径）激活促进的。我们先前的研究表明，AKT激活是由烟草成分诱导的，对于肺癌的形成，维持和化学抗性很重要。使用微阵列分析，我们表明肿瘤抑制RHOB在支气管上皮细胞中被调节，因为它们从永生化到完全转化。 Akt介导的FOXO3A的致癌抑制抑制了RHOB，FoxO3A是长寿和抑制肿瘤之间界面处的转录因子。 RHOB也以喂食方式抑制了人支气管上皮细胞中的Akt活性。 RHOB丧失是肺癌中经常发生的事件，这可能在癌变期间有助于AKT激活。此外，随着小鼠的年龄，RHOB启动子在肺组织中逐渐沉默，并在人类肺癌中表观抑制。 RHOB的等级损失可能会增加气道上皮细胞的基因组不稳定性，加速肺部衰老，并使受损细胞更容易受到癌症的进展，尤其是在暴露于香烟烟雾时。我们假设RHOB肺的丧失会促进肺部衰老和肺部肿瘤发生。我们的初步数据表明，在衰老期间，A/J小鼠的肺中RHOB蛋白会降低，并通过暴露于激活Akt的烟草致癌物NNK进一步改善。这些结果为研究RHOB在肺老化/癌症界面中的作用提供了强烈的理由，通过测试以下特定目的。具体的AIM1将研究RHOB在小鼠肺衰老和肿瘤发生中的作用。通过比较肺组织中DNA损伤和基因组不稳定的年龄依赖性变化，支气管肺泡灌洗细胞组成和炎症细胞因子的特征，以及年龄匹配，野生型和Rhob敲除LSL K-RAS K-RAS G12D C57BL/6小鼠之间的肿瘤多样性和大小，与Rhom aby Iss Iss Iss Iss Iss Iss Iss Iss Iss Iss Iss Iss Iss Iss Iss Iss Iss Iss Iss Iss Iss Inlom Iss Iss Iss Iss Is Inlom Is。在肺衰老和肺肿瘤发生期间。具体的目标2将确定老年小鼠中RHOB的重建是否可以防止肺肿瘤发生。通过在肿瘤形成之前恢复老年LSL K-RAS G12D C57BL/6的RHOB表达或烟烟暴露于烟雾的A/J肺肿瘤小鼠模型，我们将能够测试RHOB的重建是否可以预防或减轻年龄小鼠的肺肿瘤。这些创新的研究将提供有关肺衰老和肺癌发展的机械洞察力。此外，它们对通过RHOB的重新激活而对肺功能保存和预防肺癌的预防具有潜在的临床意义。