Biomarkers of Human Lung Cancer

人类肺癌的生物标志物

• 批准号: 8552870
• 负责人: Curtis Harris
• 金额: $ 80.32万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8552870
• 关键词: 3' Untranslated Regions; Age; Anchorage-Independent Growth; Binding Sites; Biological Markers; CDC2 Protein Kinase; Cell Line; Cell Proliferation; Cells; Cessation of life; Clinical; Collaborations; Cultured Cells; Cytoplasm; Databases; Development; Diagnostic; Diagnostic Neoplasm Staging; Disease; Disease Progression; ERBB2 gene; Epidermal Growth Factor Receptor; Epithelial Cells; Estrogen Receptors; Family; Formalin; Freezing; Gene Expression Profile; Genes; Goals; Human; Immigration; Immunoblotting; Japan; KRAS2 gene; Kinesin; Lead; Lung; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Messenger RNA; MicroRNAs; Microtubules; Mitosis; Molecular; Molecular Profiling; Mutation; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Oncogenes; Outcome; Paraffin Embedding; Patients; Phosphotransferases; Plasma; Play; RET Oncogene; RET gene; Resistance; Risk; Role; Sampling; Signal Pathway; Single Nucleotide Polymorphism; Smoker; Stage at Diagnosis; Staging; Stratification; Telomerase; Testing; Therapeutic; Tissue Microarray; Transcript; Tumor Suppressor Genes; Tumor Tissue; Tumor stage; Tyrosine Kinase Inhibitor; United States; burden of illness; cancer therapy; carcinogenesis; cell immortalization; cell transformation; chemotherapy; clinically relevant; clinically significant; cohort; human disease; improved; novel; prognostic; sex; therapeutic target; tumor; tumor growth

miRNA plays an important role in human disease and cancer. We seek to investigate the expression status, clinical relevance, and functional role of miRNA in non-small cell lung cancer. In collaboration with Jun Jen et al., we conducted miRNA expression profiling in matched lung adenocarcinoma and uninvolved lung using 56 pairs of fresh-frozen (FF) and 47 pairs of formalin-fixed, paraffin-embedded (FFPE) samples from never smokers. The most differentially expressed miRNA genes were evaluated by Cox analysis and log-rank test. Among the best candidate, miR-708 was further examined for differential expression in two independent cohorts. Functional significance of miR-708 expression in lung cancer was examined by identifying its candidate mRNA target and through manipulating its expression levels in cultured cells. Among the 20 miRNAs most differentially expressed between tested tumor and normal samples, high expression level of miR-708 in the tumors was most strongly associated with an increased risk of death after adjustments for all clinically significant factors including age, sex, and tumor stage (FF cohort: HR, 1.90; 95% CI, 1.08-3.35; P = 0.025 and FFPE cohort: HR, 1.93; 95% CI, 1.02-3.63; P = 0.042). The transcript for TMEM88 gene has a miR-708 binding site in its 3' UTR and was significantly reduced in tumors high of miR-708. Forced miR-708 expression reduced TMEM88 transcript levels and increased the rate of cell proliferation, invasion, and migration in culture. miRNA-708 acts as an oncogene contributing to tumor growth and disease progression by directly downregulating TMEM88, a negative regulator of the Wnt signaling pathway in lung cancer. In collaboration with Tahaski Kohno et al., we identified in-frame fusion transcripts of KIF5B (the kinesin family 5B gene) and the RET oncogene, which are present in 1-2% of lung adenocarcinomas (LADCs) from people from Japan and the United States, using whole-transcriptome sequencing. The KIF5B-RET fusion leads to aberrant activation of RET kinase and is considered to be a new driver mutation of LADC because it segregates from mutations or fusions in EGFR, KRAS, HER2 and ALK, and a RET tyrosine kinase inhibitor, vandetanib, suppresses the fusion-induced anchorage-independent growth activity of NIH3T3 cells.The dismal lethality of lung cancer is due to late stage at diagnosis and inherent therapeutic resistance. The incorporation of targeted therapies has modestly improved clinical outcomes, but the identification of new targets could further improve clinical outcomes by guiding stratification of poor-risk early stage patients and individualizing therapeutic choices. In collaboration with Phil Dennis et al., we hypothesized that a sequential, combined microarray approach would be valuable to identify and validate new targets in lung cancer. We profiled gene expression signatures during lung epithelial cell immortalization and transformation, and showed that genes involved in mitosis were progressively enhanced in carcinogenesis. 28 genes were validated by immunoblotting and 4 genes were further evaluated in non-small cell lung cancer tissue microarrays. Although CDK1 was highly expressed in tumor tissues, its loss from the cytoplasm unexpectedly predicted poor survival and conferred resistance to chemotherapy in multiple cell lines, especially microtubule-directed agents. An analysis of expression of CDK1 and CDK1-associated genes in the NCI60 cell line database confirmed the broad association of these genes with chemotherapeutic responsiveness. These results have implications for personalizing lung cancer therapy and highlight the potential of combined approaches for biomarker discovery.

miRNA在人类疾病和癌症中起重要作用。我们试图研究miRNA在非小细胞肺癌中的表达状态，临床相关性和功能作用。 与Jun Jen等人合作，我们使用56对新鲜粉状（FF）和47对福尔马林固定的，福音蛋白 - 膜状的（FFPE）（FFPE）在匹配的肺腺癌和未卷发肺中进行了miRNA表达分析。通过COX分析和对数秩检验评估了最差异表达的miRNA基因。在最佳候选者中，MiR-708进一步检查了两个独立队列中的差异表达。通过鉴定其候选mRNA靶标和操纵其在培养细胞中的表达水平，检查了miR-708表达在肺癌中的功能显着性。 在测试肿瘤和正常样品之间最差异表达的20个miRNA中，肿瘤中miR-708的高表达水平与所有临床上重要因素调整后的死亡风险增加最密切相关，包括年龄，性别和肿瘤阶段（FF同学：HR：HR：HR，1.90; 1.90; 95％CI，1.08-3.35; p = 0.025; p = 0.025; pef：coh coh; coh coh; coh coh; coh coh; pe = 0.025和fffff = 0.025; cohr; coh; coh coh; 1. HR; CI，1.02-3.63; p = 0.042）。 TMEM88基因的转录本在其3'UTR中具有miR-708结合位点，并且在高为miR-708的肿瘤中显着降低。强迫miR-708表达降低了TMEM88的转录水平，并提高了培养物中细胞增殖，侵袭和迁移的速度。 miRNA-708充当癌基因，通过直接下调TMEM88（肺癌中Wnt信号通路的负调节剂）来导致肿瘤生长和疾病进展。与Tahaski Kohno等人合作，我们确定了KIF5B（运动蛋白家族5B基因）和RET癌基因的框架内融合笔录，这些转录是使用全部转录序列的日本和美国各州的肺腺癌（LADC）中1-2％的。 KIF5B接收融合会导致RET激酶的异常激活，被认为是LADC的新驱动器突变，因为它与EGFR，KRAS，HER2和ALK中的突变或融合隔离，以及RET RET酪氨酸激酶抑制剂vandetanib，vandetanib抑制了融合诱导的NIHIHIN型nih3t损失的损坏的nih3t Cinter nih3t Cinter nih3tintal tisheration nih3t的损坏了损坏的损坏。到诊断和固有的治疗性抗性后的晚期。有针对性疗法的纳入临床结局适度改善，但是新靶标的识别可以通过指导不良风险的早期患者分层和个性化治疗选择来进一步改善临床结果。在与Phil Dennis等人的合作中，我们假设一种顺序的，合并的微阵列方法对于识别和验证肺癌的新目标是有价值的。我们在肺上皮细胞永生和转化过程中介绍了基因表达特征，并表明涉及有丝分裂的基因在癌变中逐渐增强。通过免疫印迹验证了28个基因，并在非小细胞肺癌组织微阵列中进一步评估了4个基因。尽管CDK1在肿瘤组织中高度表达，但其细胞质的损失意外地预测了多种细胞系（尤其是微管指导剂）中对化学疗法的耐药性差。 NCI60细胞系数据库中CDK1和CDK1相关基因表达的分析证实了这些基因与化学治疗反应性的广泛关联。这些结果对个性化肺癌疗法具有影响，并突出了生物标志物发现合并方法的潜力。

项目成果

Circulating micro-RNA expression profiles in early stage nonsmall cell lung cancer.

• DOI: 10.1002/ijc.26153
• 发表时间: 2012-03-15
• 期刊: INTERNATIONAL JOURNAL OF CANCER
• 影响因子: 6.4
• 作者: Heegaard, Niels H. H.;Schetter, Aaron J.;Welsh, Judith A.;Yoneda, Mitsuhiro;Bowman, Elise D.;Harris, Curtis C.
• 通讯作者: Harris, Curtis C.

The association of microRNA expression with prognosis and progression in early-stage, non-small cell lung adenocarcinoma: a retrospective analysis of three cohorts.

• DOI: 10.1158/1078-0432.ccr-10-2961
• 发表时间: 2011-04-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Saito M;Schetter AJ;Mollerup S;Kohno T;Skaug V;Bowman ED;Mathé EA;Takenoshita S;Yokota J;Haugen A;Harris CC
• 通讯作者: Harris CC

Frequent homozygous deletion of the LKB1/STK11 gene in non-small cell lung cancer.

• DOI: 10.1038/onc.2011.98
• 发表时间: 2011-09-01
• 期刊: Oncogene
• 影响因子: 8
• 作者: Gill RK;Yang SH;Meerzaman D;Mechanic LE;Bowman ED;Jeon HS;Roy Chowdhuri S;Shakoori A;Dracheva T;Hong KM;Fukuoka J;Zhang JH;Harris CC;Jen J
• 通讯作者: Jen J

MicroRNA expression and clinical outcomes in patients treated with adjuvant chemotherapy after complete resection of non-small cell lung carcinoma.

• DOI: 10.1158/0008-5472.can-10-1348
• 发表时间: 2010-11-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Voortman J;Goto A;Mendiboure J;Sohn JJ;Schetter AJ;Saito M;Dunant A;Pham TC;Petrini I;Lee A;Khan MA;Hainaut P;Pignon JP;Brambilla E;Popper HH;Filipits M;Harris CC;Giaccone G
• 通讯作者: Giaccone G

EGFR somatic mutations in lung tumors: radon exposure and passive smoking in former- and never-smoking U.S. women.

肺癌中的 EGFR 体细胞突变：曾经吸烟和从不吸烟的美国女性的氡暴露和被动吸烟。

• DOI: 10.1158/1055-9965.epi-12-0166
• 发表时间: 2012
• 期刊: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
• 作者: Taga,Masataka;Mechanic,LeahE;Hagiwara,Nobutoshi;Vähäkangas,KirsiH;Bennett,WilliamP;Alavanja,MichaelCR;Welsh,JudithA;Khan,MohammedA;Lee,Adam;Diasio,Robert;Edell,Eric;Bungum,Aaron;Jang,JinSung;Yang,Ping;Jen,Jin;Harris,
• 通讯作者: Harris,