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）：肺癌是美国和全世界男性和女性癌症死亡的主要原因。肿瘤抑制基因 LKB1 是一种编码丝氨酸/苏氨酸激酶的基因，对细胞代谢、极性至关重要。和生长控制 - 在大约 30% 的非小细胞肺癌 (NSCLC) 病例中体细胞失活，将其列为 NSCLC 中第三个最常见的突变基因。 KRAS 突变会促进小鼠模型中的肺癌转移，并且与不良预后相关。LKB1 状态与小鼠肿瘤模型中的多种靶向药物和化疗的反应有关，因此，LKB1 可以作为人类的诊断、预后和预测生物标志物。然而，在利用 LKB1 缺陷获得临床益处之前，我们需要可靠的检测方法对 LKB1 功能丧失的肿瘤进行评分，并进一步了解 LKB1 肿瘤抑制功能的分子基础及其临床。近年来，长非编码 RNA (lncRNA) 已成为一类新型基因调节因子，并且与肿瘤发生有关。我们在一组中观察到 lncRNA (LINC00473) 的表达上调与 LKB1 失活之间存在密切相关性。此外，LKB1 的过度表达降低了 LINC00473 的表达，而 LKB1 的缺失则增强了它的表达。重要的是，我们的初步研究显示其表达量较高。 LINC00473 在 LKB1 蛋白下调的人原发性肺肿瘤中的表达从功能上来说，LINC00473 的缺失降低了肺癌细胞的增殖和存活。这一假设将通过两个具体目标来解决，目标 1 将研究 LKB1 调节的分子机制。 LINC00473 表达并评估 LINC00473 作为 LKB1 失活肺癌生物标志物的上调。目标 2 将确定 LINC00473 在调节肺癌中的作用和机制。这些目标的成功完成将为了解 LINC00473 的作用和机制提供重要见解。肺癌发生中的作用，并有可能揭示肺癌的新生物标志物和潜在治疗靶点。