RRC ID 54478
Author Matsushita A, Sato T, Mukai S, Fujishita T, Mishiro-Sato E, Okuda M, Aoki M, Hasegawa Y, Sekido Y.
Title TAZ activation by Hippo pathway dysregulation induces cytokine gene expression and promotes mesothelial cell transformation.
Journal Oncogene
Abstract 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.
Volume 38(11)
Pages 1966-1978
Published 2019-3-1
DOI 10.1038/s41388-018-0417-7
PII 10.1038/s41388-018-0417-7
PMID 30401981
MeSH Animals Cell Line, Tumor Cell Transformation, Neoplastic / genetics* Cytokines / genetics* Cytokines / metabolism Epithelium / metabolism Epithelium / pathology Female Gene Expression Regulation, Neoplastic Hippo Signaling Pathway Humans Intracellular Signaling Peptides and Proteins / genetics* Intracellular Signaling Peptides and Proteins / metabolism Lung Neoplasms / genetics* Lung Neoplasms / metabolism Lung Neoplasms / pathology Mesothelioma / genetics* Mesothelioma / metabolism Mesothelioma / pathology Mesothelioma, Malignant Mice Mice, Nude Protein Serine-Threonine Kinases / genetics* Protein Serine-Threonine Kinases / metabolism Signal Transduction / genetics Trans-Activators Transcription Factors / genetics* Transcription Factors / metabolism Transcriptional Activation Transcriptional Coactivator with PDZ-Binding Motif Proteins
IF 6.634
Times Cited 6
DNA material pKM2L-phIL1B (RDB05526)