The Wnt and Prostacyclin pathways act in concert to inhibit NSCLC cell growth

Wnt 和前列环素途径协同作用抑制 NSCLC 细胞生长

• 批准号: 8047429
• 负责人: Robert A. Winn
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8047429
• 关键词: Actinin; Anchorage-Independent Growth; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Appearance; Asbestos; Biological; Biological Assay; Breast Melanoma; Cancer Etiology; Carcinogens; Caring; Cell Culture Techniques; Cell Line; Cell Polarity; Cell Proliferation; Cells; Cessation of life; Chemopreventive Agent; Colon; Colorectal Cancer; Development; Disease; Distal; E-Cadherin; Early Diagnosis; Eicosanoids; Epithelium; Epoprostenol; Exposure to; Future; Goals; Human; Iloprost; Immunohistochemistry; In Vitro; Investigation; Knockout Mice; Laboratories; Lead; Lung; Lung Neoplasms; MAPK8 gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Medical; Medical Research; Methylation; Military Personnel; Mission; Modification; Molecular; Molecular Target; Mus; Mutation; N-Cadherin; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Oral; PPAR gamma; Pathway interactions; Patient Care; Patients; Phase II Clinical Trials; Phenotype; Play; Population; Predisposition; Property; Prostacyclin synthase; Prostaglandins I; Research; Research Priority; Role; Screening procedure; Services; Signal Pathway; Signal Transduction; Smoke; Smoker; Smoking Prevention; Snails; Staging; Supplementation; Survival Rate; Tail; Testing; Therapeutic; Tobacco Dependence; Troponin I; Troponin T; Tumor Suppressor Genes; Tumor Suppressor Proteins; United States; Urethane; Veins; Veterans; Woman; Work; abstracting; agent orange; analog; base; beta catenin; cancer therapy; cell growth; cell transformation; chemical carcinogen; cigarette smoking; connectin; epithelial to mesenchymal transition; genetic regulatory protein; high risk; improved; in vivo; lung Carcinoma; lung carcinogenesis; malignant breast neoplasm; member; men; migration; overexpression; plakoglobin; prevent; promoter; receptor; response; restoration; small hairpin RNA; smoking cessation; success; therapeutic target; tobacco abuse; tumor; tumorigenic

DESCRIPTION (provided by applicant): Abstract: Lung cancer is the number one cause of cancer death in both men and women in the United States. In fact, more deaths will occur this year from lung cancer than breast, prostate, and colorectal cancers combined. Lung cancer has been identified as a medical priority for the Department of Veterans affairs due to the high rates of tobacco addiction acquired by military personnel. The cumulative five-year survival rate for lung cancer remains approximately 15%, thus improved success in decreasing death from lung cancer will rely not only on smoking prevention and cessation, but the future development of molecular therapeutic targets for treatment. The Wnt signaling pathway, is a highly conserved signaling pathway that is critical for normal development and mutation of specific components has been implicated in many human cancers including colon, breast, and melanoma, but has yet to be fully examined in detail in lung cancers. The overall goal of this study is to determine the role of Fzd 9 (2-catenin independent) signaling on the initiation and promotion of NSCLC. Our findings to date suggest two seemingly unrelated Fzd 9 functions: 1) that Fzd 9 participates in acting as a tumor suppressor in normal lung epithelia, and 2) that activation of Fzd 9 activates 2-catenin independent (non-canonical) Wnt signaling through its interactions with both the Wnt 7a and prostacyclin pathways, inducing activation of the tumor suppressor gene PPAR3. In previous work, we have demonstrated that Wnt 7a and/or Fzd 9 expression is frequently reduced in NSCLC, and that the loss of Wnt 7a and/or Fzd 9 is strongly associated with epithelial to mesenchymal transition (EMT), loss of cellular polarity, and increased susceptibility to lung carcinogensis in mice. In addition, we have also discovered that prostacyclin and its synthetic analog iloprost are able to mimic many of the effects of Wnt 7a. We hypothesize that Fzd 9 is part of an important tumor suppressor gene pathway, and it's lost will lead to increased EMT and/or transformation in non-transformed lung cultured cell lines. In addition, we have previously demonstrated that with restoration of Fzd 9 in NSCLC we could reverse the transformed phenotype, by inducing a number of downstream tumor suppressor targets. Thus we hypothesize that loss of Fzd 9 in normal lung will result in decreased signaling of the tumor suppressive effects. Lastly, we also hypothesize that the mechanism by which iloprost/Fzd 9 inhibits NSCLC cell growth is similar to that of the Wnt 7a/Fzd 9 PUBLIC HEALTH RELEVANCE: Investigations into molecular cancer therapy of lung cancer are directly relevant to the Department of Veterans' Affairs patient care mission, as lung cancer is a Veterans' Affairs medical research priority. Lung cancer is the leading cause of cancer death in the veteran population. While tobacco abuse is currently discouraged by the military, there still exists a very large percentage of high-risk current and former smokers cared for by the VA that might benefit from advances in therapeutic molecular targeting in lung cancer. Agent Orange and asbestos exposure, well-established lung carcinogens, are service-connected disorders and have strongly been associated with lung cancer. Research investigating the mechanisms and strategies for lung cancer molecular therapeutic therapy has tremendous potential benefit to veterans, many of whom no longer smoke, yet remain at high risk for lung cancer.

描述（由申请人提供）： 翻译后摘要：肺癌是癌症死亡的头号原因，在美国的男性和女性。事实上，今年死于肺癌的人数将超过乳腺癌、前列腺癌和结直肠癌的总和。肺癌已被确定为退伍军人事务部的医疗优先事项，因为军人吸烟成瘾的比例很高。肺癌的累积五年生存率仍然约为15%，因此，降低肺癌死亡率的成功率不仅取决于预防吸烟和戒烟，还取决于未来分子治疗靶点的发展。Wnt信号通路是一种高度保守的信号通路，其对于特定组分的正常发育和突变至关重要，已经涉及许多人类癌症，包括结肠癌、乳腺癌和黑色素瘤，但尚未在肺癌中进行充分详细的研究。本研究的总体目标是确定Fzd 9（2-连环蛋白非依赖性）信号传导在NSCLC的启动和促进中的作用。迄今为止，我们的研究结果表明两种看似无关的Fzd 9功能：1）Fzd 9参与作为正常肺上皮细胞中的肿瘤抑制因子，2）Fzd 9的激活通过与Wnt 7a和前列环素途径的相互作用激活2-连环蛋白非依赖性（非经典）Wnt信号传导，诱导肿瘤抑制基因PPAR 3的激活。在以前的工作中，我们已经证明，Wnt 7a和/或Fzd 9的表达在NSCLC中经常减少，并且Wnt 7a和/或Fzd 9的缺失与小鼠的上皮细胞向间质细胞转化（EMT）、细胞极性丧失和对肺癌易感性增加密切相关。此外，我们还发现前列环素及其合成类似物伊洛前列素能够模拟Wnt 7a的许多作用。我们假设Fzd 9是一个重要的肿瘤抑制基因通路的一部分，它的丢失将导致非转化肺培养细胞系中EMT和/或转化的增加。此外，我们先前已经证明，通过在NSCLC中恢复Fzd 9，我们可以通过诱导许多下游肿瘤抑制靶点来逆转转化的表型。因此，我们假设正常肺中Fzd 9的缺失将导致肿瘤抑制作用的信号传导减少。最后，我们还假设伊洛前列素/Fzd 9抑制NSCLC细胞生长的机制与Wnt 7a/Fzd 9相似。 公共卫生相关性： 肺癌的分子癌症治疗的调查是直接相关的退伍军人事务部的病人护理使命，因为肺癌是退伍军人事务部医学研究的优先事项。肺癌是退伍军人癌症死亡的主要原因。虽然军方目前不鼓励烟草滥用，但仍有很大比例的高风险当前和以前的吸烟者受到退伍军人事务部的照顾，他们可能会从肺癌治疗分子靶向的进步中受益。橙子剂和石棉暴露是公认的肺癌致癌物，是与服务有关的疾病，与肺癌密切相关。研究肺癌分子治疗的机制和策略对退伍军人有巨大的潜在益处，他们中的许多人不再吸烟，但仍然处于肺癌的高风险之中。