TAZ activation by Hippo pathway dysregulation induces cytokine gene expression and promotes mesothelial cell transformation

Our plain-English summary of TAZ activation by Hippo pathway dysregulation induces cytokine gene expression and promotes mesothelial cell transformation, by A. Matsushita, T. Sato, S. Mukai, et al (Oncogene, 2019).

The study

• Authors: A. Matsushita, T. Sato, S. Mukai, T. Fujishita, E. Mishiro-Sato, M. Okuda, M. Aoki, Y. Hasegawa, Y. Sekido
• Journal: Oncogene
• Published: 2019;38(11):1966-1978
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

In plain English

This laboratory study examined the role of the transcriptional coactivator TAZ, regulated by the Hippo pathway, in malignant mesothelioma cell lines, immortalized mesothelial cell lines and nude mice. The authors reported that 14 of 23 malignant mesothelioma cell lines (61%) expressed more TAZ than YAP, and that 15 (65%) of 23 showed underphosphorylated (activated) TAZ, whereas TAZ was strongly phosphorylated in the immortalized MeT-5A and HOMC-D4 mesothelial cells. Knocking down TAZ with shRNA reduced proliferation, anchorage-independent growth, motility and invasion in Y-MESO-27 cells, but did not suppress proliferation of ACC-MESO-1 or NCI-H2452 cells, which had more phosphorylated TAZ. Introducing an activated TAZ mutant (S89A) into HOMC-D4 mesothelial cells increased these properties and produced calretinin-positive tumours invading subpleural tissue after implantation into the thoracic cavity of nude mice. Microarray analysis pointed to cytokine genes; IL1A, IL1B and IL6 messenger RNA were 4–8-fold higher in HOMC-D4 cells expressing TAZ-S89A than in those expressing wild-type TAZ, and blocking IL1B or using an IL-1 receptor antagonist suppressed growth of TAZ-activated cells.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: laboratory (in vitro cell line and mouse xenograft) experimental study
• Who was studied: Human malignant mesothelioma cell lines (23 analysed for TAZ status), immortalized mesothelial cell lines MeT-5A and HOMC-D4, and six-week-old female nude mice; work carried out at Aichi Cancer Center, Japan
• Exposure: No asbestos was applied; the manipulated factors were TAZ status (shRNA knockdown, wild-type TAZ or constitutively active TAZ-S89A lentivirus), IL1B knockdown, recombinant IL-1beta (10 ng/mL) and IL-1 receptor antagonist (up to 100 ng/mL)
• Main results:
  • Over half of the mesothelioma cell lines expressed more TAZ than YAP (14 of 23, 61%)
  • 15 of 23 (65%) mesothelioma cell lines showed underphosphorylated (activated) TAZ, unlike the immortalized mesothelial lines
  • TAZ knockdown in Y-MESO-27 cells reduced proliferation, anchorage-independent growth, motility and invasion, but did not suppress proliferation of ACC-MESO-1 or NCI-H2452 cells with inactivated TAZ
  • Activated TAZ-S89A, but not wild-type TAZ, made immortalized HOMC-D4 mesothelial cells tumorigenic in the thoracic cavity of nude mice, with calretinin-positive invasion of subpleural tissue
  • In TAZ-S89A-expressing HOMC-D4 cells, mRNA of IL1A, IL1B and IL6 was 4-8-fold higher than in wild-type TAZ-expressing cells
  • IL-1 receptor antagonist inhibited proliferation of TAZ-S89A-expressing HOMC-D4 cells (about 50% inhibition at 100 ng/mL) but not parental or wild-type TAZ cells, nor mesothelioma cells without TAZ activation
• The authors' conclusion: The authors concluded that TAZ, like YAP, contributes to malignant phenotypes of mesothelioma cells with Hippo pathway inactivation and might be a molecular target in such tumours, with IL-1 signalling as one key downstream cascade
• Limitations the authors state:
  • The authors stated that equivalent protein levels of activated YAP and activated TAZ were not rigorously confirmed when comparing their effects on interleukin gene expression
  • The authors noted that questions remain, including why YAP and TAZ differ in expression and activation between individual mesothelioma cell lines, and whether the TAZ-IL1beta axis matters in other tumours
  • The animal experiments were not randomized and investigators were not blinded

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Cytokine, Mesothelial Cells, Malignant Mesothelioma, Asbestos Exposure, Latency, Tumor Suppressor Gene, Hippo Signaling Pathway.

Related studies

• The Emerging Role of the Hippo Pathway in Lung Cancers: Clinical Implications — S.L. Teoh, S. Das (2017)
• Immunohistochemistry for NF2, LATS1/2, and YAP/TAZ Fails to Separate Benign From Malignant Mesothelial Proliferations — B.S. Sheffield, J. Lorette, et al. (2016)
• Aberrant expression of NPPB through YAP1 and TAZ activation in mesothelioma with Hippo pathway gene alterations — T. Sato, K. Akao, et al. (2023)
• Inactivation of Merlin in malignant mesothelioma cells and the Hippo signaling cascade dysregulation — Y. Sekido (2011)
• Hippo pathway gene mutations in malignant mesothelioma: revealed by RNA and targeted exon sequencing — A. Miyanaga, M. Masuda, et al. (2015)
• LIM-domain protein AJUBA suppresses malignant mesothelioma cell proliferation via Hippo signaling cascade — I. Tanaka, H. Osada, et al. (2015)

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