Novel mechanisms of oncogenic transformation in lung cancer

肺癌致癌转化的新机制

• 批准号: 8753300
• 负责人: CHRISTINE M. EISCHEN
• 金额: $ 32.58万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8753300
• 关键词: Accounting; Address; Adenocarcinoma; Adenocarcinoma Cell; Anchorage-Independent Growth; Binding; Biochemistry; Biological Assay; Biological Markers; Biological Process; Cancer Etiology; Carcinoma; Cell Line; Cell physiology; Cells; Cellular biology; Clinical; Colon Carcinoma; Data; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Early Diagnosis; Ensure; Epidermal Growth Factor Receptor; Epithelial Cell Proliferation; Epithelial Cells; Evaluation; Event; Functional RNA; Gene Mutation; Genes; Genetic; Growth Factor; Guanosine Triphosphate Phosphohydrolases; Human; Hyperplasia; In Vitro; Individual; Investigation; KRAS2 gene; Knowledge; Lead; Left; Light; Link; Lung; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Biology; Molecular Genetics; Mus; Mutate; Mutation; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Oncogenes; Oncogenic; Pathway interactions; Patients; Process; Prognostic Marker; Proteins; Ras Signaling Pathway; Regulation; Role; Sampling; Signal Pathway; Signal Transduction; Staging; Technology; Testing; Transgenic Mice; United States; Up-Regulation; Xenograft Model; adenoma; bone; cancer initiation; feeding; in vivo; killings; lung tumorigenesis; malignant breast neoplasm; mortality; mouse model; mutant; new therapeutic target; novel; novel diagnostics; outcome forecast; overexpression; protein expression; public health relevance; research study; tumor; tumorigenesis

DESCRIPTION (provided by applicant): More people in the US die from lung cancer than from breast, prostate and colon cancer combined. Specific oncogenes, such as the growth factor signaling GTPase KRAS, are mutated and constitutively active in lung cancers. Although it is clear oncogenic proteins can drive lung cancer development, there is incomplete understanding of the molecular and genetic events that result in this process and in the initiation and progression of lung cancers. microRNA (miRNA), non-coding RNA that regulate protein expression, have been linked to cellular processes involved in tumor development and progression. We postulated that specific miRNA that are overexpressed in lung cancer may function as oncogenes themselves or cooperate with known oncogenes in the initiation of this malignancy. To determine whether specific miRNA have an oncogenic role in lung adenocarcinoma, the most common lung cancer, we investigated miRNA expression. Altered levels of specific miRNA were detected in lung adenocarcinoma, and one particular miRNA was overexpressed in a panel of lung adenocarcinoma cells lines that also contained activating mutations of KRAS. Notably, elevated levels of this miRNA were detected in human lung adenocarcinoma patient samples and this correlated with disease stage. Overexpression of this miRNA in untransformed human lung epithelial cells resulted in increased proliferation and anchorage-independent growth. Inhibition of this miRNA in human lung adenocarcinoma cells suppressed proliferation and overexpression induced tumor formation in a xenograft model. Importantly, in a novel, newly generated mouse model, inducible expression of this miRNA in the lungs rapidly led to hyperplasia and adenoma development. We have also identified multiple negative regulators of RAS pathway signaling as targets of this miRNA. Therefore, we hypothesize this miRNA is a novel driver of lung adenocarcinoma initiation through modulation of the RAS oncogenic signaling pathway and that it cooperates with mutant KRAS in lung cancer development. We propose to test this hypothesis with three Specific Aims. In Aim 1, we will use the novel lung specific inducible miRNA mouse to evaluate the effects of increased expression of this miRNA on lung cancer initiation and its contribution to mutant KRAS-driven lung cancer. In Aim 2, we will investigate the negative regulators of the oncogenic RAS pathway as targets of the specific miRNA, and we will identify novel targets that contribute to early and late changes in the lung during adenocarcinoma initiation and progression. In Aim 3, we will determine the genetic mutations in human lung cancer and the signaling pathways that regulate the expression of this miRNA. The integration of mouse models, patient samples, molecular biology, biochemistry, and cell biology proposed in this application will significantly increase understanding of the contribution of miRNA to lung adenocarcinoma and the molecular events that lead to the initiation of this deadly disease. Results from these studies are also likely to identify novel therapeutic targets and diagnostic and prognostic markers for lung adenocarcinoma.

描述（由申请人提供）：在美国，死于肺癌的人数比死于乳腺癌、前列腺癌和结肠癌的人数总和还要多。特定的癌基因，例如生长因子信号传导 GTP 酶 KRAS，在肺癌中发生突变并持续活跃。尽管很明显致癌蛋白可以驱动肺癌的发展，但对导致这一过程以及肺癌发生和进展的分子和遗传事件尚不完全了解。 microRNA (miRNA) 是调节蛋白质表达的非编码 RNA，与肿瘤发生和进展的细胞过程有关。我们推测，在肺癌中过度表达的特定 miRNA 本身可能充当癌基因，或者与已知的癌基因协同作用，引发这种恶性肿瘤。为了确定特定 miRNA 是否在最常见的肺癌——肺腺癌中具有致癌作用，我们研究了 miRNA 的表达。在肺腺癌中检测到特定 miRNA 水平的改变，并且一种特定 miRNA 在一组也含有 KRAS 激活突变的肺腺癌细胞系中过度表达。值得注意的是，在人类肺腺癌患者样本中检测到该 miRNA 水平升高，并且这与疾病阶段相关。该 miRNA 在未转化的人肺上皮细胞中过度表达导致增殖和贴壁依赖性生长增加。抑制人肺腺癌细胞中的这种 miRNA 可抑制异种移植模型中的增殖和过度表达诱导的肿瘤形成。重要的是，在一个新生成的小鼠模型中，这种 miRNA 在肺部的诱导表达迅速导致了增生和腺瘤的发展。我们还确定了 RAS 通路信号传导的多个负调节因子作为该 miRNA 的靶标。因此，我们假设该 miRNA 是通过调节 RAS 致癌信号通路启动肺腺癌的新驱动因素，并且它在肺癌发展中与突变的 KRAS 协同作用。我们建议通过三个具体目标来检验这一假设。在目标 1 中，我们将使用新型肺特异性诱导 miRNA 小鼠来评估该 miRNA 表达增加对肺癌发生的影响及其对突变 KRAS 驱动的肺癌的贡献。在目标 2 中，我们将研究致癌 RAS 通路的负调节因子作为特定 miRNA 的靶点，并且我们将确定有助于腺癌发生和进展过程中肺部早期和晚期变化的新靶点。在目标 3 中，我们将确定人类肺癌的基因突变以及调节该 miRNA 表达的信号通路。本申请中提出的小鼠模型、患者样本、分子生物学、生物化学和细胞生物学的整合将显着增进对 miRNA 对肺腺癌的贡献以及导致这种致命疾病发生的分子事件的理解。这些研究的结果也有可能确定肺腺癌的新治疗靶点以及诊断和预后标志物。