Role of Id1 in NSCLC Progression and Metastasis

Id1 在 NSCLC 进展和转移中的作用

• 批准号: 8385488
• 负责人: SRIKUMAR P. CHELLAPPAN
• 金额: $ 32.29万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8385488
• 关键词: Accounting; Adenocarcinoma; Affect; Apoptotic; Biology; Breast; Carcinogens; Cell Proliferation; Cell Survival; Cells; DNA Damage; Data; Development; Disease; EGF gene; Epidermal Growth Factor Receptor; Exposure to; Functional disorder; Genes; Growth; Health; Helix-Turn-Helix Motifs; Human; In Vitro; Invaded; Lead; Lung; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mediator of activation protein; Molecular; Molecular Profiling; Mutation; Neoplasm Metastasis; Nicotine; Nicotinic Receptors; Non-Small-Cell Lung Carcinoma; Oncogenes; Pancreas; Pathway interactions; Patients; Phosphotransferases; Play; Primary Neoplasm; Proliferating; Property; Prostate; Proteins; RAS genes; Reporting; Role; STAT3 gene; Sampling; Signal Pathway; Signal Transduction; Signaling Molecule; Smoker; Smoking; Squamous cell carcinoma; Structure of parenchyma of lung; System; TP53 gene; Therapeutic Agents; Time; Tissues; Tobacco; Tobacco use; Tobacco-Associated Carcinogen; Transcription Repressor/Corepressor; Tumor Promoters; Vascular Endothelial Growth Factors; angiogenesis; base; cancer type; cigarette smoking; cigarette smoking; combat; in vivo; matrigel; migration; mortality; mouse model; neoplastic cell; non-smoker; novel; novel therapeutics; outcome forecast; overexpression; prevent; response; tissue/cell culture; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Non-small cell lung carcinoma (NSCLC) is highly correlated with smoking and smokers constitute about 75% of NSCLC patients. Many tobacco-specific carcinogens present in cigarette smoke cause DNA damage, leading to the mutation of vital genes like Ras, p53 and Rb. In addition, many of these tobacco carcinogens as well as nicotine itself can promote cell proliferation and angiogenesis through the activation of nicotinic acetylcholine receptors (nAChRs). NSCLC in smokers and non-smokers are qualitatively different and have different molecular signatures; for example, cancers in non-smokers predominantly have mutations in the kinase domain of EGFR. There are also histological distinctions between NSCLC in smokers and non-smokers, the former being predominantly squamous cell carcinomas and the latter mainly adenocarcinomas. Nevertheless, NSCLC in both the groups of patients are highly metastatic, leading to mortality. Given the fact that the primary cells of the lung that give rise to these tumors can proliferate in response to signals transduced through nicotinic acetylcholine receptors as well as EGFR, and since tumor cells derived from these tissues actively divide and invade in response to nAChR and EGFR signaling, we hypothesize that there might be common mediators of these signals in smokers and non-smokers. Specifically, we propose that the helix-loop- helix protein Id1 is a common mediator of proliferation, invasion and angiogenesis in NSCLC in smokers and non-smokers. Id1 is known to play a significant role in the progression and metastasis of a variety of tumors, including those of breast, prostate and pancreas; at the same time, little is known about its potential role in the biology of NSCLC. Our preliminary data shows that Id1 is induced in NSCLC cells in response to nAChR as well as EGFR signaling and that depletion of Id1 prevents nicotine and EGF-induced proliferation and invasion. Depletion of Id1 also greatly reduced nicotine and VEGF-induced angiogenic tubule formation in matrigel. Further, Id1 was elevated in human NSCLC samples, with maximal amount present in metastatic tumors. We hypothesize that both nAChRs and EGFR induce Id1 in a Src and STAT3-dependent fashion and contributes to the invasive and metastatic properties of these cancers. Based on these observations, we propose three specific aims: (1) To assess whether Id1 is a common mediator of NSCLC growth in response to nicotinic receptor and EGFR signaling (2) To evaluate the role of Id1 in nAChR-induced angiogenesis and metastasis (3) To evaluate the contribution of Id1 to the growth and metastasis of NSCLC in smokers and non-smokers and to assess whether elevated Id1 correlates with poor prognosis. We believe that these studies will identify novel pathways that are involved in the genesis and progression of non-small cell lung cancers and will lead to the development of novel therapeutic agents to combat this disease.

描述（由申请人提供）：非小细胞肺癌（NSCLC）与吸烟高度相关，吸烟者约占NSCLC患者的75%。香烟烟雾中存在的许多烟草特异性致癌物会导致DNA损伤，导致Ras、p53和Rb等重要基因突变。此外，许多这些烟草致癌物质以及尼古丁本身都可以通过激活尼古丁乙酰胆碱受体（nictinicacetylcholine receptor, nAChRs）促进细胞增殖和血管生成。吸烟者和非吸烟者的非小细胞肺癌在质量上存在差异，具有不同的分子特征；例如，非吸烟者的癌症主要在EGFR的激酶结构域发生突变。吸烟者和非吸烟者的非小细胞肺癌在组织学上也存在差异，前者主要为鳞状细胞癌，后者主要为腺癌。然而，两组患者的NSCLC都是高度转移的，导致死亡。考虑到产生这些肿瘤的肺原代细胞可以响应烟碱乙酰胆碱受体和EGFR转导的信号而增殖，并且由于来自这些组织的肿瘤细胞响应nAChR和EGFR信号而积极分裂和侵袭，我们假设吸烟者和非吸烟者中可能存在这些信号的共同介质。具体来说，我们提出螺旋-环-螺旋蛋白Id1是吸烟者和非吸烟者非小细胞肺癌中增殖、侵袭和血管生成的共同介质。已知Id1在多种肿瘤的进展和转移中发挥重要作用，包括乳腺、前列腺和胰腺肿瘤；同时，对其在非小细胞肺癌生物学中的潜在作用知之甚少。我们的初步数据显示，Id1在NSCLC细胞中响应nAChR和EGFR信号而被诱导，并且Id1的耗尽可以阻止尼古丁和egf诱导的增殖和侵袭。Id1的缺失也大大减少了尼古丁和vegf诱导的基质血管生成小管的形成。此外，Id1在人类非小细胞肺癌样本中升高，在转移性肿瘤中含量最高。我们假设nachr和EGFR都以Src和stat3依赖的方式诱导Id1，并有助于这些癌症的侵袭性和转移性。基于这些观察结果，我们提出了三个具体目的：(1)评估Id1是否是响应尼古丁受体和EGFR信号的非小细胞肺癌生长的共同介质(2)评估Id1在nachr诱导的血管生成和转移中的作用(3)评估Id1在吸烟者和非吸烟者中对非小细胞肺癌生长和转移的贡献，以及评估Id1升高是否与不良预后相关。我们相信，这些研究将确定参与非小细胞肺癌发生和发展的新途径，并将导致开发新的治疗药物来对抗这种疾病。

项目成果

Nicotine-mediated invasion and migration of non-small cell lung carcinoma cells by modulating STMN3 and GSPT1 genes in an ID1-dependent manner.

• DOI: 10.1186/1476-4598-13-173
• 发表时间: 2014-07-16
• 期刊: Molecular cancer
• 影响因子: 37.3
• 作者: Nair S;Bora-Singhal N;Perumal D;Chellappan S
• 通讯作者: Chellappan S

Influence of secreted frizzled receptor protein 1 (SFRP1) on neoadjuvant chemotherapy in triple negative breast cancer does not rely on WNT signaling.

• DOI: 10.1186/1476-4598-13-174
• 发表时间: 2014-07-17
• 期刊: Molecular cancer
• 影响因子: 37.3
• 作者: Bernemann C;Hülsewig C;Ruckert C;Schäfer S;Blümel L;Hempel G;Götte M;Greve B;Barth PJ;Kiesel L;Liedtke C
• 通讯作者: Liedtke C

Nicotine induces inhibitor of differentiation-1 in a Src-dependent pathway promoting metastasis and chemoresistance in pancreatic adenocarcinoma.

• DOI: 10.1593/neo.121044
• 发表时间: 2012-12
• 期刊: Neoplasia
• 影响因子: 4.8
• 作者: J. Trevino;S. Pillai;Sateesh S. Kunigal;S. Singh;W. Fulp;B. Centeno;S. Chellappan

Gli1-Mediated Regulation of Sox2 Facilitates Self-Renewal of Stem-Like Cells and Confers Resistance to EGFR Inhibitors in Non-Small Cell Lung Cancer.

• DOI: 10.1016/j.neo.2015.07.001
• 发表时间: 2015-07
• 期刊: Neoplasia (New York, N.Y.)
• 作者: Bora-Singhal N;Perumal D;Nguyen J;Chellappan S
• 通讯作者: Chellappan S