Abstract
TAZ, also known as WWTR1, has recently been suggested as an oncogene in non-small cell lung cancer (NSCLC). We investigated the clinical relevance of TAZ expression and its functional role in NSCLC tumorigenesis. We characterized TAZ at the DNA (n=192), mRNA (n=196), and protein levels (n=345) in an NSCLC patient cohort. Gene expression analysis was complemented by a meta-analysis of public datasets (n=1,382). The effects of TAZ on cell proliferation and cell cycle were analyzed in cell cultures and on tumor growth in mice. TAZ-dependent microarray-based expression profiles in NSCLC cells were combined with molecular profiles in human NSCLC tissues for in silico analysis. Higher TAZ mRNA and protein levels were associated with shorter patient survival. Transduction of TAZ enhanced cell proliferation and tumorigenesis in bronchial epithelial cells, whereas TAZ silencing suppressed cell proliferation and induced cell cycle arrest in NSCLC cells. Microarray and cell culture experiments showed that ErbB ligands (amphiregulin, epiregulin, and neuregulin 1) are downstream targets of TAZ. Our in silico analysis revealed a TAZ signature that substantiated the clinical impact of TAZ and confirmed its relationship to the epidermal growth factor receptor signaling pathway. TAZ expression defines a clinically distinct subgroup of patients with NSCLC. ErbB ligands are suggested to mediate the effects of TAZ on lung cancer progression. Our findings emphasize the tumorigenic role of TAZ and may serve as the basis for new treatment strategies.
Highlights
Lung cancer is the leading cause of cancer-related death worldwide
Higher transcriptional coactivator with PDZ-binding motif (TAZ) mRNA and protein levels were associated with shorter patient survival
TAZ gene expression levels were lower in tumor samples harboring epidermal growth factor receptor (EGFR) mutations than in EGFR/KRAS mutation-negative samples (P 1⁄4 0.046, Supplementary Fig. S1A)
Summary
Lung cancer is the leading cause of cancer-related death worldwide. Despite the high histologic heterogeneity, the overall prognosis for lung cancer is extremely poor, with non–small cell lung cancer (NSCLC) representing 85% of all diagnosed cases [1]. Zation of human cancer tissues, distinct molecular aberrations have been identified in small subgroups of patients and are being successfully exploited for therapeutic intervention, including epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase, and c-ros oncogene 1 fusion proteins [2, 3]. For the vast majority of patients, treatment options are scant and the overall prognosis remains poor, emphasizing the need to uncover additional molecular mechanisms important in lung cancer tumorigenesis. The regulation of TAZ and its paralog, Yes-associated protein (YAP), occurs primarily via the Hippo pathway, which is conserved from flies to humans [5]. TAZ has been suggested to be involved in other biologic processes, including mesenchymal stem cell differentiation via modulation of Runx2- and PPARg-dependent gene expression [7], self-renewal of human embryonic stem cells via regulation of the localization of Smad [8], and mechanotransduction [9].
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