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

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头号原因。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。由于军人吸烟率高，肺癌已被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保持在15%左右，因此，减少肺癌死亡的成功不仅取决于吸烟的预防和戒烟，而且取决于未来治疗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，对正常发育至关重要，特定成分的突变与包括结肠癌、乳腺癌和黑色素瘤在内的许多人类癌症有关，但在肺癌中尚未得到充分的详细研究。本研究的总体目标是确定FZD-9(2-连环蛋白非依赖性)信号在非小细胞肺癌的启动和促进中的作用。到目前为止，我们的发现提示了两个似乎不相关的FZD 9功能：1)FZD 9参与作为正常肺上皮细胞的肿瘤抑制因子，以及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-连环素独立(非典型的)Wnt信号，诱导肿瘤抑制基因PPAR3的激活。在以前的工作中，我们已经证明Wnt7a和/或Fzd9在NSCLC中的表达经常降低，并且Wnt7a和/或Fzd9的缺失与小鼠上皮向间充质转化(EMT)、细胞极性丧失以及肺癌易感性的增加密切相关。此外，我们还发现前列环素及其合成类似物iloprost能够模拟Wnt7a的许多作用。我们推测FZD-9是一个重要的抑癌基因通路的一部分，它的缺失将导致未转化的肺培养细胞系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，我们可以通过诱导一些下游的肿瘤抑制靶点来逆转转化的表型。因此，我们假设FZD-9在正常肺中的缺失将导致肿瘤抑制效应的信号减弱。最后，我们还假设，iloprost/Fzd 9抑制NSCLC细胞生长的机制与Wnt 7a/Fzd 9相似

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