Aberrant expression of NPPB through YAP1 and TAZ activation in mesothelioma with Hippo pathway gene alterations

Our plain-English summary of Aberrant expression of NPPB through YAP1 and TAZ activation in mesothelioma with Hippo pathway gene alterations, by T. Sato, K. Akao, A. Sato, et al (Cancer Medicine, 2023).

The study

• Authors: T. Sato, K. Akao, A. Sato, T. Tsujimura, S. Mukai, Y. Sekido
• Journal: Cancer Medicine
• Published: 2023;12(12):13586-13598
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Mesothelioma is a neoplastic disease associated with asbestos exposure. It is highly malignant and has a poor prognosis; thus, early detection is desirable. Recent whole-genome analysis has revealed that mesothelioma is characterized by a high frequency of mutations in a set of genes involved in the Hippo pathway, such as NF2 and LATS2. However, a rapid, simple, and precise method for finding mesothelioma with these mutations has not yet been established.

Methods: Clustering of Hippo pathway gene alteration groups and the differential expression of each gene in mesothelioma patients were analyzed using The Cancer Genome Atlas database. Gene expression levels in various tumors and normal tissues were analyzed using public databases. Knockdown or transient expression of YAP1 or TAZ was performed to evaluate the regulation of gene expression by these genes. NT-proBNP was measured in the pleural effusions of 18 patients and was compared with NF2 expression in five cases where cell lines had been successfully established.

Results: NPPB mRNA expression was markedly higher in the group of mesothelioma patients with Hippo pathway gene mutations than in the group without them. NPPB expression was low in all normal tissues except heart, and was highest in mesothelioma. Mesothelioma patients in the high NPPB expression group had a significantly worse prognosis than those in the low NPPB expression group. NPPB expression was suppressed by knockdown of YAP1 or TAZ. NT-proBNP was abundant in the effusions of mesothelioma patients and was particularly high in those with impaired NF2 expression.

Conclusions: NPPB, whose levels can be measured in pleural effusions of mesothelioma patients, has the potential to act as a biomarker to detect NF2-Hippo pathway gene alterations and/or predict patient prognosis. Additionally, it may provide useful molecular insights for a better understanding of mesothelioma pathogenesis and for the development of novel therapies.

© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

In plain English

This laboratory and database study examined NPPB, which makes the heart-failure marker BNP, in mesothelioma, not asbestos exposure. From public genetic data, the authors compared patients with and without changes in the Hippo pathway genes NF2, LATS1 or LATS2. The article reports this altered group as 35 of 82, though it describes 87 samples. NPPB gene expression was more than 13-fold higher in the altered group. Among 32 cancer types it was highest in mesothelioma; normal tissues except heart rarely expressed it. Median overall survival was 12.7 months (95% CI, 9.3 to 15.1) with high NPPB versus 26.1 months (95% CI, 19.4 to 31.2) with low. In cultured mesothelioma cells, reducing YAP1 or TAZ levels lowered NPPB expression and BNP release. Pleural-fluid NT-proBNP in 18 patients ranged 18 to 4841 pg/mL. Of five cases yielding cell lines, the one with normal NF2 was below the median and four with reduced or absent NF2 above it, too few to test statistically. The authors concluded NPPB may be a biomarker for these gene changes and/or prognosis. They lacked data on patients' heart function.

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 study combining analysis of public gene-expression databases, cell-line experiments, and measurement of NT-proBNP in patients' pleural fluid
• Who was studied: 87 mesothelioma samples from The Cancer Genome Atlas (TCGA-MESO) cohort; 9279 TCGA tumors across 32 cancer types; normal tissues from the GTEx database; pleural effusions from 18 mesothelioma patients, five of which yielded cell lines; mesothelioma cell lines NCI-H2052 and NCI-H2373 and immortalized mesothelial cells HOMC-D4
• Exposure: Not asbestos. The study examined genetic alterations (mutations, deletions or gene fusions) in the Hippo pathway genes NF2, LATS1 and LATS2, and NPPB gene expression
• Main results:
  • NPPB gene expression was more than 13-fold higher in the group with Hippo pathway gene alterations than in the Unaltered group (TCGA-MESO); the article reports the Altered group as 35/82 patients although it describes an 87-sample cohort
  • Among TCGA tumors across 32 cancer types, NPPB was strongly suppressed in most types but strongly expressed in mesothelioma; it was rarely expressed in normal tissues except the heart
  • Median overall survival was 26.1 months (95% CI, 19.4 to 31.2) in the low-NPPB group and 12.7 months (95% CI, 9.3 to 15.1) in the high-NPPB group
  • Median progression-free survival was 16.7 months (95% CI, 13.3 to 26.2) in the low-NPPB group and 10.3 months (95% CI, 6.6 to 14.7) in the high-NPPB group
  • Median overall survival in the Altered and Unaltered groups was 13.4 and 23.3 months; the difference was not statistically significant (p = 0.0952)
  • Patients with Hippo pathway or CDKN2A gene alterations were significantly more common in the high-NPPB group (p = 0.0003 and 0.0002); BAP1 mutations did not differ between groups
  • In NCI-H2373 mesothelioma cells, knockdown of YAP1 or TAZ decreased NPPB expression and BNP secretion into the culture medium
  • NPPB knockdown did not suppress proliferation in cells with NF2 or LATS2 gene alterations
  • In pleural effusions from 18 mesothelioma patients, NT-proBNP ranged from 18 to 4841 pg/mL, with a median of 212.5 pg/mL. Among the five cases with established cell lines, the sample with normal NF2 was below the median and those with low or undetectable NF2 were above it. No statistical test was performed.
  • The TEAD inhibitor K-975 suppressed NPPB mRNA more strongly than ANKRD1 mRNA in treated cells
• The authors' conclusion: The authors concluded that NPPB transcription and secretion of BNP and NT-proBNP were enhanced in mesothelioma with Hippo pathway gene alterations, that high NPPB expression was associated with poor prognosis, and that further studies are needed
• Limitations the authors state:
  • BNP and NT-proBNP rise in heart failure, but the authors could not collect sufficient information on patients' cardiovascular function
  • Statistical tests on pleural-fluid NT-proBNP versus NF2 could not be performed because few cell lines were established
  • It remains unclear whether Hippo pathway gene changes or NPPB mRNA levels correlate with NT-proBNP synthesis or secretion into pleural effusions
  • The authors' experiments did not confirm that NPPB directly promotes mesothelioma cell proliferation
  • Molecules in the Hippo pathway are not well defined, so the impact of known genetic variants on the pathway is hard to judge
  • The authors had not yet found an antibody that can measure BNP levels in tissue by immunohistochemistry

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma, Pleural plaques and thickening.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Asbestos Exposure, Prognosis, Pleural Effusion, Biomarker.

Related studies

• TAZ activation by Hippo pathway dysregulation induces cytokine gene expression and promotes mesothelial cell transformation — A. Matsushita, T. Sato, et al. (2019)
• Hippo pathway gene mutations in malignant mesothelioma: revealed by RNA and targeted exon sequencing — A. Miyanaga, M. Masuda, et al. (2015)
• The hippo pathway provides novel insights into lung cancer and mesothelioma treatment — X.L. Liu, R. Zuo, et al. (2018)
• A Succinate Ether Derivative of Tocotrienol Enhances Dickkopf-1 Gene Expression through Epigenetic Alterations in Malignant Mesothelioma Cells — A. Sato, H. Ueno, et al. (2018)
• The Emerging Role of the Hippo Pathway in Lung Cancers: Clinical Implications — S.L. Teoh, S. Das (2017)
• LIM-domain protein AJUBA suppresses malignant mesothelioma cell proliferation via Hippo signaling cascade — I. Tanaka, H. Osada, et al. (2015)

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