Inactivation of Merlin in malignant mesothelioma cells and the Hippo signaling cascade dysregulation

Our plain-English summary of Inactivation of Merlin in malignant mesothelioma cells and the Hippo signaling cascade dysregulation, by Y. Sekido (Pathology International, 2011).

The study

• Author: Y. Sekido
• Journal: Pathology International
• Published: 2011;61(6):331-44
• Type of article: Review
• Cited by: 67 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma (MM) is an aggressive tumor arising primarily from pleural or peritoneal cavities, which is caused by asbestos exposure after long latency. One of the most frequently mutated genes detected in MM cells is the neurofibromatosis type 2 (NF2) tumor suppressor gene which is located at chromosome 22q12. The NF2 gene encodes Merlin, an ERM (Ezrin/Radixin/Moesin) protein. The underphosphorylated form of Merlin is active and acts as a tumor suppressor by regulating several distinct cellular signaling pathways. One of the downstream pathways regulated by Merlin is the Hippo signaling pathway, which is conserved from Drosophila to mammalian cells and plays important roles in organ size control and cancer development. Recent studies have identified alterations of the components in the Hippo signaling cascade in MM cells, including overexpression of Yes-associated protein (YAP) and inactivation of large tumor suppressor homolog 2 (LATS2). Dysregulation of the Merlin-Hippo signaling cascade is one of the frequent and key events of MM cell development and/or progression. Thus, a strategy to normalize this signaling cascade may be the rationale for developing a new target therapy against MM.

© 2011 The Author. Pathology International © 2011 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd.

In plain English

This article is a review, not a new study. The author summarized published laboratory research on the NF2 gene, which makes a protein called Merlin, in malignant mesothelioma. The review also covered a cell-growth control system that Merlin influences, called the Hippo signaling pathway. According to the studies reviewed, NF2 is inactivated by mutation or deletion in 40–50% of mesotheliomas. In one mouse study described in the review, asbestos-exposed mice carrying one inactivated Nf2 copy developed mesothelioma much faster than asbestos-treated normal mice. Among the findings on human material that the review cited, a Hippo-pathway protein called YAP was found in more than 70% of primary mesothelioma tissues. In 20 mesothelioma cell lines, four had lost both copies of the LATS2 gene and three had a point mutation or small deletion in it. The author concluded that restoring normal function of this pathway seems to be a promising strategy for developing new targeted drugs. The author also noted that many questions about the pathway remain unresolved.

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: Narrative review of published laboratory research (cell lines, tumor tissue and mouse models) on Merlin/NF2 and the Hippo signaling pathway in malignant mesothelioma
• Who was studied: No study population of its own; the review drew on published studies of mesothelioma cell lines, primary mesothelioma tissues and genetically altered mice
• Exposure: Asbestos is described as the cause of mesothelioma after a long latency; reviewed mouse studies exposed Nf2-altered and normal mice to asbestos, including crocidolite injected into the abdomen
• Main results:
  • Reviewed studies report that NF2 is inactivated by mutation or by deletion of both copies in 40–50% of malignant mesotheliomas
  • In a reviewed mouse study, loss of the remaining normal Nf2 copy was found in all asbestos-induced mesotheliomas from Nf2 (+/-) mice and in 50% of mesotheliomas from asbestos-exposed normal (wild-type) mice
  • In a cited study, YAP was detected by tissue staining in more than 70% of primary mesothelioma tissues
  • In a cited study of 20 mesothelioma cell lines, four had deletion of both copies of LATS2 and three had a point mutation or small deletion of LATS2; LATS2 staining was negative or low in around 30% of mesotheliomas
  • In reviewed experiments, adding NF2 to mesothelioma cells increased YAP phosphorylation and moved YAP from the nucleus to the cytoplasm
• The authors' conclusion: The author concluded that normalizing the disrupted Merlin-Hippo signaling seems to be a promising strategy for developing new targeted drugs against mesothelioma
• Limitations the authors state:
  • The author states that citations for many observations were left out because of restrictions on review manuscripts
  • The author states that Merlin's functions have not been clearly determined, so it is unclear which other molecules may substitute for NF2 inactivation
  • The author notes unresolved questions about the pathway's role, including why some cell lines carry both NF2 and LATS2 mutations

Topics

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

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

Related studies

• LIM-domain protein AJUBA suppresses malignant mesothelioma cell proliferation via Hippo signaling cascade — I. Tanaka, H. Osada, et al. (2015)
• TAZ activation by Hippo pathway dysregulation induces cytokine gene expression and promotes mesothelial cell transformation — A. Matsushita, T. Sato, et al. (2019)
• Convergent signaling in the regulation of connective tissue growth factor in malignant mesothelioma: TGFβ signaling and defects in the Hippo signaling cascade — M. Fujii, H. Nakanishi, et al. (2012)
• Merlin, a "magic" linker between extracellular cues and intracellular signaling pathways that regulate cell motility, proliferation, and survival — I. Stamenkovic, Q. Yu (2010)
• NF2/Merlin Inactivation and Potential Therapeutic Targets in Mesothelioma — T. Sato, Y. Sekido (2018)
• Functional inactivation of NF2/merlin in human mesothelioma — C. Thurneysen, I. Opitz, et al. (2009)

Browse more research in Pathology International, or return to medical research.