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Malignant mesothelioma (MM) constitutes a very aggressive tumor that is caused by asbestos exposure after long latency. The NF2 tumor suppressor gene is mutated in 40-50% of MM; moreover, one of its downstream signaling cascades, the Hippo signaling pathway, is also frequently inactivated in MM cells. Although the YAP transcriptional coactivator, which is regulated by the Hippo pathway, can function as a pro-oncogenic protein, the role of TAZ, a paralog of YAP, in MM cells has not yet been clarified. Here, we show that TAZ is expressed and underphosphorylated (activated) in the majority of MM cells compared to immortalized mesothelial cells. ShRNA-mediated TAZ knockdown highly suppressed cell proliferation, anchorage-independent growth, cell motility, and invasion in MM cells harboring activated TAZ. Conversely, transduction of an activated form of TAZ in immortalized mesothelial cells enhanced these in vitro phenotypes and conferred tumorigenicity in vivo. Microarray analysis determined that activated TAZ most significantly enhanced the transcription of genes related to "cytokine-cytokine receptor interaction." Among selected cytokines, we found that IL-1 signaling activation plays a major role in proliferation in TAZ-activated MM cells. Both IL1B knockdown and an IL-1 receptor antagonist significantly suppressed malignant phenotypes of immortalized mesothelial cells and MM cells with activated TAZ. Overall, these results indicate an oncogenic role for TAZ in MMs via transcriptional induction of distinct pro-oncogenic genes including cytokines. Among these, IL-1 signaling appears as one of the most important cascades, thus potentially serving as a target pathway in MM cells harboring Hippo pathway inactivation.

Malignant mesothelioma (MM) is an aggressive tumor commonly caused by asbestos exposure after a long latency. Focal adhesion kinase (FAK) inhibitors inhibit the cell growth of Merlin-deficient MM cells; however, their clinical efficacy has not been clearly determined. The aim of this study was to evaluate the growth inhibitory effect of the FAK inhibitor VS-4718 on MM cell lines and identify biomarkers for its efficacy. Although most Merlin-deficient cell lines were sensitive to VS-4718 compared with control MeT-5A cells, a subset of these cell lines exhibited resistance to this drug. Microarray and qRT-PCR analyses using RNA isolated from Merlin-deficient MM cell lines revealed a significant correlation between E-cadherin mRNA levels and VS-4718 resistance. Merlin- and E-cadherin-negative Y-MESO-22 cells underwent apoptosis upon treatment with a low concentration of VS-4718, whereas Merlin-negative, E-cadherin-positive Y-MESO-9 cells did not undergo VS-4718-induced apoptosis. Furthermore, E-cadherin knockdown in Merlin-negative MM cells significantly sensitized cells to VS-4718 and induced apoptotic cell death upon VS-4718 treatment. Together, our results suggest that E-cadherin serves as a predictive biomarker for molecular target therapy with FAK inhibitors for patients with mesothelioma and that its expression endows MM cells with resistance to FAK inhibitors.