Role of the noncanonical WNT pathway in non-small cell lung cancer

描述（由申请人提供）：肺癌仍然是世界上男性和女性癌症死亡的主要原因，非小细胞肺癌（NSCLC）占肺癌的大多数。近80%的肺癌是在晚期不能手术的阶段被诊断出来的，目前的全身治疗对肺癌患者的益处有限。本研究的总体目标是确定？-catenin独立（即非规范）Wnt信号在NSCLC的启动和促进中的作用。到目前为止，我们的研究结果表明两个看似不相关的Wnt 7a功能：1)Wnt 7a在正常肺上皮中作为肿瘤抑制因子，2)激活Wnt 7a激活？-catenin独立（非规范）Wnt信号通过Fzd9，诱导肿瘤抑制基因PPAR的激活。在之前的研究中，我们已经证明Wnt 7a和/或Fzd 9的表达在NSCLC中经常降低，并且Wnt 7a和/或Fzd 9的缺失与小鼠上皮到间充质转化（EMT）、细胞极性丧失和肺癌易感性增加密切相关。基于这些发现，我们假设Wnt 7a/Fzd9信号在建立和/或维持细胞极性中起着新的作用，并通过调节非典型Wnt (？-catenin独立)信号。此外，我们最近发现Wnt 7a在人肺癌中频繁的启动子甲基化，使Wnt 7a成为未来治疗非小细胞肺癌的潜在治疗靶点。

DESCRIPTION (provided by applicant): Lung cancer remains the leading cause of cancer death in the world for both men and women, and non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer. Nearly 80% of lung cancer is diagnosed at an advanced inoperable stage, and current systemic therapy offers only modest benefits for lung cancer patients. The overall goal of this study is to determine the role of ?-catenin independent (i.e. non-canonical) Wnt signaling on the initiation and promotion of NSCLC. Our findings to date suggest two seemingly unrelated Wnt 7a functions: 1) that Wnt 7a acts as a tumor suppressor in normal lung epithelia, and 2) that activation of Wnt 7a activates ?-catenin independent (non-canonical) Wnt signaling through Fzd9, inducing activation of the tumor suppressor gene PPAR?. 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 carcinogenesis in mice. Based on these findings, we hypothesize that Wnt 7a/Fzd9 signaling plays a novel role in establishing and/or maintaining cell polarity, and functions as a tumor suppressor in the lung epithelium by regulating non- canonical Wnt (?-catenin independent) signaling. Moreover, our recent finding of frequent promoter methylation of Wnt 7a in human lung cancer makes Wnt 7a a potentially attractive future therapeutic target in the treatment of NSCLC. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer death for both men and women in the United States. In fact, more deaths will occur this year due to lung cancer than breast, prostate, and colorectal cancers combined. The experimental strategies outlined in this project are designed to evaluate the contribution of the non-canonical Wnt pathway to lung cancer and to identify genetic targets of this pathway that could be used to develop potential small molecular therapeutic targets for the treatment of lung cancer.