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: 8289263
• 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/8289263
• 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

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。实际上，与乳腺癌，前列腺和结直肠癌相比，今年肺癌的死亡人数将更多。由于军事人员获得的烟草成瘾率很高，因此已将肺癌确定为退伍军人事务部的医疗优先事项。肺癌的累积五年存活率仍然约为15％，因此改善了减少肺癌死亡的成功，不仅将依赖于预防吸烟和停止，而且还依赖于分子治疗靶点的未来治疗靶标。 Wnt信号通路是一种高度保守的信号通路，对正常发育至关重要，并且特定成分的突变与许多人类癌症有关，包括结肠癌，乳腺癌和黑色素瘤，但尚未在肺癌中进行详细检查。这项研究的总体目标是确定FZD 9（2-catenin独立）信号传导对NSCLC的启动和促进的作用。 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.在先前的工作中，我们已经证明了NSCLC中经常降低Wnt 7a和/或FZD 9的表达，并且Wnt 7a和/或FZD 9的丧失与上皮上皮与间质转变（EMT），细胞极性丧失，肺癌的易感性有关。此外，我们还发现，前列环素及其合成类似物依前列素能够模仿Wnt 7a的许多效果。我们假设FZD 9是重要的肿瘤抑制基因途径的一部分，并且它丢失将导致非转化的肺培养细胞系中EMT增加和/或转化。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标来逆转转化的表型。因此，我们假设正常肺中FZD 9的丧失将导致肿瘤抑制作用的信号降低。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