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: 8398949
• 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/8398949
• 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; 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; screening; 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

描述（由申请人提供）： 摘要：肺癌是美国男性和女性癌症死亡的第一大原因。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。由于军人烟草成瘾率很高，肺癌已被确定为退伍军人事务部的医疗重点。肺癌的累积五年生存率仍约为15%，因此，降低肺癌死亡率的成功不仅取决于预防和戒烟，还取决于未来分子治疗靶点的开发。 Wnt信号通路是一条高度保守的信号通路，对正常发育至关重要，其特定成分的突变与许多人类癌症（包括结肠癌、乳腺癌和黑色素瘤）有关，但在肺癌中尚未得到充分详细的研究。本研究的总体目标是确定 Fzd 9（不依赖 2-连环蛋白）信号传导在 NSCLC 发生和促进中的作用。迄今为止，我们的研究结果表明 Fzd 9 具有两个看似无关的功能：1）Fzd 9 参与正常肺上皮细胞中的肿瘤抑制因子的作用，2）Fzd 9 的激活通过 2-连环蛋白独立（非典型）Wnt 信号传导激活它与 Wnt 7a 和前列环素途径相互作用，诱导肿瘤抑制基因 PPAR3 的激活。在之前的工作中，我们已经证明 Wnt 7a 和/或 Fzd 9 表达在 NSCLC 中经常降低，并且 Wnt 7a 和/或 Fzd 9 的缺失与上皮间质转化 (EMT)、细胞极性丧失密切相关，并增加小鼠患肺癌的易感性。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仿Wnt 7a的许多作用。我们假设 Fzd 9 是重要的肿瘤抑制基因途径的一部分，它的丢失将导致非转化肺培养细胞系的 EMT 和/或转化增加。此外，我们之前已经证明，随着 NSCLC 中 Fzd 9 的恢复，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弱。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。