Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression

Abstract

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. In this report, we show that the Wnt pathway is 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 biological significance of Wnt signaling and, in particular, Dvl function in lung cancer, we transfected siRNA (designed to inhibit selectively human Dvl-1, -2, and -3), to the NSCLC cell line H1703, which is known to have bcatenin-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 inhibition. Taken together, these data support the novel hypothesis that Dvl overexpression is critical to Wnt signaling activation and cell growth in NSCLC.

Inhibition of Wnt16 in human acute lymphoblastoid leukemia cells containing the t(1;19) translocation induces apoptosis

“…The proto-oncogenic effects of Wnt were discovered more than 20 years ago (Nusse and Varmus, 1982) and since then numerous reports have demonstrated aberrant activation of the Wnt signaling pathway in disparate human cancers (Morin et al, 1997;Rhee et al, 2002;Weeraratna et al, 2002). We reported the overexpression of dishevelled (Dvl) proteins in thoracic malignancies (Uematsu et al, 2003a, b). It is also known that Wnt proteins regulate early B-cell growth and survival (Reya et al, 2003) and the activation of the Wnt signaling pathway has been demonstrated in chronic lymphocytic leukemia (Lu et al, 2004).…”

Challenge and promise: roles for Livin in progression and therapy of cancer

“…A second posttranscriptional network indicates that Livin is involved in the wingless and integration site growth factor (Wnt)/h-catenin signaling pathway, the key component of which involves h-catenin activation of genes that have significant consequences on tumor development by forming a complex with the T-cell factor (TCF) transcription factor family (39). In human non -small cell lung cancer A549 and 103H cell lines, the activity of the Livin promoter was increased considerably by h-catenin activation and could be blocked by a dominant-negative TCF expression construct.…”

Constitutive activation of the Wnt/β-catenin signalling pathway in acute myeloid leukaemia

“…These prevent phosphorylation or ubiquitination of b-catenin and are often found in colorectal tumours that do not have mutations in APC (Giles et al, 2003;Kikuchi, 2003). Recently, overexpression of Dsh has been implicated in the development of mesothelioma and lung cancer (Uematsu et al, 2003a, b).…”