A novel noncoding RNA and human lung cancers with inactivated LKB1 signaling

一种新型非编码 RNA 与 LKB1 信号失活的人类肺癌

• 批准号: 8881623
• 负责人: Lizi Wu
• 金额: $ 19.11万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-21 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8881623
• 关键词: Address; Biological Assay; Biological Markers; CREB1 gene; Cancer Etiology; Cancer cell line; Cell Proliferation; Cell Survival; Cessation of life; Clinical; Cyclic AMP; DNA Sequence Alteration; Data; Detection; Development; Diagnostic; Epigenetic Process; Evaluation; Event; Freezing; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Growth; Human; In Vitro; KRAS2 gene; Link; Lung Adenocarcinoma; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metabolism; Microarray Analysis; Modeling; Molecular; Mus; Mutate; Mutation; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Normal Cell; Oncogenes; Pathway interactions; Patients; Pilot Projects; Protein-Serine-Threonine Kinases; Proteins; Regulation; Regulator Genes; Research; Role; STK11 gene; Signal Transduction; Stratification; Structure; Technology; Testing; Transcriptional Activation; Tumor Suppressor Proteins; United States; Untranslated RNA; Up-Regulation; Validation; Vision; Woman; accurate diagnosis; base; cancer cell; cell behavior; chemotherapy; cohort; digital; functional loss; gene function; in vivo; insight; lung tumorigenesis; men; mouse model; nano-string; novel; outcome forecast; overexpression; prognostic; public health relevance; rapid diagnosis; response; therapeutic target; tumor; tumorigenesis

 DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer deaths in both men and women in the United States and worldwide. The tumor suppressor LKB1 gene - a gene encoding a serine/threonine kinase that is critical for cellular metabolism, polarity and growth control - is somatically inactivated in approximately 30% of non small cell lung cancer (NSCLC) cases, ranking it as the third most frequently mutated gene in NSCLC. The loss of LKB1 in the context of KRAS mutations promotes lung cancer metastasis in mouse models, and is associated with poor prognosis. The LKB1 status is linked with cancer responsiveness to several targeted agents and chemotherapy in mouse tumor models. LKB1 is thus implicated as diagnostic, prognostic and predictive biomarkers in human lung cancer. However, before clinical benefits that exploit LKB1 deficiency can be achieved, we need to have reliable assays to score tumors with LKB1 functional loss and to further understand the molecular basis for LKB1 tumor suppressor function and its clinical implications. Long noncoding RNAs (lncRNAs) have emerged as a novel class of gene regulators in recent years and are implicated in oncogenesis. We have observed a tight correlation between up-regulated expression of a lncRNA (LINC00473) and LKB1 inactivation in a panel of human NSCLC cell lines. Moreover, overexpression of LKB1 decreased LINC00473 expression, while LKB1 depletion enhanced it. Importantly, our pilot study revealed high LINC00473 expression in human primary lung tumors with downregulated LKB1 protein. Functionally, LINC00473 depletion reduced lung cancer cell proliferation and survival. Our overall preliminary data led us to hypothesize that LKB1 inactivation mediates LINC00473 transcriptional up-regulation and that the induced LINC00473 up-regulation contributes to lung tumorigenesis. This hypothesis will be addressed by two specific aims. Aim 1 will investigate molecular mechanisms underlying LKB1 regulation of LINC00473 expression and assess LINC00473 up-regulation as a biomarker for LKB1-inactivated lung cancers. Aim 2 will determine the role and mechanisms of LINC00473 in regulating lung cancer. The successful completion of these aims will provide significant insights into the roles and mechanisms of LINC00473 in lung tumorigenesis and has the potential to reveal novel biomarkers and potential therapeutic targets for lung cancer.

 描述（由申请人提供）：肺癌是美国和世界范围内男性和女性癌症死亡的主要原因。肿瘤抑制基因LKB 1是一种编码丝氨酸/苏氨酸激酶的基因，对细胞代谢、极性和生长控制至关重要，在约30%的非小细胞肺癌（NSCLC）病例中体细胞失活，是NSCLC中第三大最常见的突变基因。在KRAS突变的背景下，LKB 1的缺失促进小鼠模型中的肺癌转移，并且与不良预后相关。在小鼠肿瘤模型中，LKB 1状态与癌症对几种靶向药物和化疗的反应性有关。因此，LKB 1被认为是人类肺癌的诊断、预后和预测生物标志物。然而，在利用LKB 1缺陷获得临床益处之前，我们需要可靠的检测方法来评估LKB 1功能丧失的肿瘤，并进一步了解LKB 1肿瘤抑制功能的分子基础及其临床意义。长链非编码RNA（lncRNA）是近年来出现的一类新的基因调控因子，与肿瘤发生密切相关。我们已经观察到一组人NSCLC细胞系中lncRNA（LINC 00473）的上调表达与LKB 1失活之间的紧密相关性。此外，LKB 1的过度表达降低LINC 00473的表达，而LKB 1耗尽增强it. Importantly，我们的初步研究揭示了LINC 00473在人类原发性肺肿瘤与下调LKB 1蛋白的表达。在功能上，LINC 00473消耗降低肺癌细胞增殖和存活。我们的总体初步数据使我们假设LKB 1失活介导LINC 00473转录上调，并且诱导的LINC 00473上调有助于肺肿瘤发生。这一假设将通过两个具体目标来解决。目的1将研究LKB 1调控LINC 00473表达的分子机制，并评估LINC 00473上调作为LKB 1失活肺癌的生物标志物。目的2：探讨LINC 00473对肺癌的调控作用及其机制。这些目标的成功完成将为深入了解LINC 00473在肺癌发生中的作用和机制提供重要见解，并有可能揭示肺癌的新生物标志物和潜在治疗靶点。