SHORT REPORTS Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression Kazutsugu Uematsu 1,2 , Biao He 1 , Liang You 1 , Zhidong Xu 1 , Frank McCormick 1 and David Mark Jablons* ,1 1 Thoracic Oncology Laboratory, UCSF Cancer Center, University of California at San Francisco, San Francisco, CA 94115, USA; 2 The Fourth Department of Internal Medicine, Nippon Medical School, Tokyo 113-8602, Japan Non small cell lung cancer (NSCLC) is the leading cause of cancer deaths in the United States and worldwide. Unfortunately, standard therapies remain inadequate. An increased understanding of the molecular biology of lung cancer biology is required to develop more effective new therapies.Inthisreport,weshowthattheWntpathwayis activated through Dishevelled (Dvl) overexpression in NSCLC. Analysis of freshly resected tumors and lung cancer cell lines demonstrate that Dvl-3, a critical mediator of Wnt signaling, is overexpressed. Specifically, Dvl-3 was overexpressed significantly in 75% of fresh NSCLC microdissected samples compared to control paired matched normal lung samples. To evaluate the biologicalsignificanceofWntsignalingand,inparticular, Dvl function in lung cancer, we transfected siRNA (designed to inhibit selectively human Dvl-1, -2, and -3), totheNSCLCcelllineH1703,whichisknowntohave b- catenin-mediated Tcf-dependent transcriptional activity. Here, we demonstrate that Dvl-specific siRNA treatment in H1703 decreases significantly Dvl and b-catenin expression, resulting in reduction of Tcf-dependent transcriptional activity, and, importantly, growth inhibi- tion. Taken together, these data support the novel hypothesis that Dvl overexpression is critical to Wnt signaling activation and cell growth in NSCLC. Oncogene (2003) 22, 7218–7221. doi:10.1038/sj.onc.1206817 Keywords: Dishevelled (Dvl); Wnt signaling; non small cell lung cancer; siRNA Introduction, results, and discussion Lung cancer is the leading cause of cancer deaths in the United States and worldwide, with 4170000 newly diagnosed cases each year in the US and nearly million cases worldwide (Minna, 1998). Despite progress in the multimodality treatment of lung cancer in the past several decades, the 5-year survival rate for lung cancer remains poor at o15% (Minna, 1998). Surgery, chemotherapy, and radiation have been used with generally unsatisfactory results in advanced disease. Even completely resected early stage (stage I) lung cancer has a cure rate of only 60–70%, significantly less than other early stage I cancers. Improvement in the efficacy of lung cancer treatment is a major public health goal. New therapies based on a better understanding of the biology of lung cancer are necessary. Lung cancers are divided into two major histological classes: non small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC (75–80% of all lung cancers) consists of three major types: adenocarcinoma, squa- mous cell carcinoma, and large cell carcinoma (Sekido et al., 1998). Lung adenocarcinomas and squamous cell carcinomas represent 60–70% of all lung cancers. The molecular pathogenesis of lung cancer includes altera- tion of expression and function of multiple genes including dominant oncogenes and recessive onco- genes/tumor-suppressor genes, alterations in growth- regulatory signaling pathways, and abnormalities in other pathways. We and others have investigated the role of the Wnt pathway and identified Wnt signaling in thoracic malignancies. Activation of Wnt signaling appears to play an important role in carcinogenesis (Morin, 1999; Polakis, 2000). Recently, we found that overexpression of Dishevelled (Dvl), which is a critical mediator of Wnt signaling, is a dominant event in another thoracic malignancy, namely malignant pleural mesothelioma (You et al., 2001). In mesothelioma, it appears to induce tumorigenicity via a canonical Wnt signaling pathway. Wnt signaling to date has been reported to be occasionally involved in lung carcinogenesis (Sunaga et al., 2001; Ueda et al., 2001; Hommura et al., 2002; Winn et al., 2002). Interestingly, a recent report identified Wnt signaling in lung cancer cell lines that corroborated active canonical Wnt signaling (Winn et al., 2002). Most of these reports, however, have focused on b-catenin activity only to evaluate the activity of Wnt signaling. Owing to our observation that upstream events like Dvl activation play a critical role in mesothelioma growth, we sought to determine if Dvl expression might also be relevant in NSCLC. In this Received 4 April 2003; revised 8 May 2003; accepted 15 May 2003 *Correspondence: DM Jablons, University of California at San Francisco, Campus Box 1674, 1600 Divisadero St., Suite 322C, San Francisco, CA 94115, USA; E-mail: JablonsD@surgery.ucsf.edu Oncogene (2003) 22, 7218–7221 & 2003 Nature Publishing Group All rights reserved 0950-9232/03 $25.00 www.nature.com/onc