An Integrative Analysis of the Tumorigenic Role of TAZ in Human Non-Small Cell Lung Cancer

• Published in: Clinical cancer research Vol. 20; no. 17; pp. 4660 - 4672
• Main Authors: NOGUCHI, Satoshi, SAITO, Akira, LOHR, Miriam, EDLUND, Karolina, BOTLING, Johan, MICKE, Patrick, NAGASE, Takahide, HORIE, Masafumi, MIKAMI, Yu, SUZUKI, Hiroshi I, MORISHITA, Yasuyuki, OHSHIMA, Mitsuhiro, ABIKO, Yoshimitsu, MATTSSON, Johanna Sofia Margareta, KÖNIG, Helena
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.09.2014
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Carcinogenesis - genetics; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cell Proliferation - genetics; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins - biosynthesis; Intracellular Signaling Peptides and Proteins - genetics; Kaplan-Meier Estimate; Medical sciences; Mice; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Pharmacology. Drug treatments; Pneumology; Signal Transduction - genetics; Tumors; Tumors of the respiratory system and mediastinum; Human; Lung disease; Respiratory disease; Lung cancer; Bronchus disease; Tumorigenicity; Malignant tumor; non-small cell lung carcinoma; Cancer
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.ccr-13-3328

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.