A novel link between FMR gene and the JNK pathway provides clues to possible role in malignant pleural mesothelioma

Our plain-English summary of A novel link between FMR gene and the JNK pathway provides clues to possible role in malignant pleural mesothelioma, by A. Srivastava (FEBS Open Bio, 2015).

The study

• Author: A. Srivastava
• Journal: FEBS Open Bio
• Published: 2015;5:705-11
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive form of thoracic cancer with poor prognosis. While some studies have identified the molecular alterations associated with MPM, little is known about their role in MPM. For example, fragile X mental retardation (FMR) gene is up-regulated in MPM but its role in MPM is unknown. Here, utilizing Drosophila genetics, I investigate the possible role FMR may be playing in MPM. I provide evidence which suggests that FMR may contribute to tumorigenesis by up-regulating a matrix metalloprotease (MMP) and by degrading the basement membrane (BM), both important for tumor metastasis. I also demonstrate a novel link between FMR and the JNK pathway and suggest that the effects of FMR in MPM could in part be mediated by up-regulation of the JNK pathway.

In plain English

This was a laboratory study in Drosophila melanogaster carried out to explore what the fragile X mental retardation (FMR) gene, reported by others to be up-regulated in malignant pleural mesothelioma (MPM), might do. Using the UAS-Gal4 system, the author over-expressed the Drosophila FMR gene (dFMR) in the developing wing imaginal disc. Over-expression with a Ptc-Gal4 driver reduced the tissue between wing veins 3 and 4 (n = >50 flies, complete penetrance), and a Vg-Gal4 driver produced wing notches, phenotypes the author described as indicative of cell death. A puc-lacZ reporter showed beta-galactosidase activity in the dFMR-expressing domain, read as up-regulation of the JNK pathway. Immunostaining showed up-regulation of MMP1, and the dFMR-expressing cells left the anterior-posterior boundary and migrated into the posterior compartment. Using a viking-GFP (collagen IV) trap, modest, incompletely penetrant basement membrane degradation was seen, mainly in the wing disc hinge. dFMR over-expression did not cooperate with activated RasV12 (data not shown). The author proposed, as speculative, that FMR may contribute to MPM tumorigenesis partly through JNK up-regulation.

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: Experimental laboratory study using Drosophila melanogaster genetics (transgenic over-expression in wing imaginal discs)
• Who was studied: Drosophila melanogaster: adult wings and third instar larval wing imaginal discs of defined genotypes, raised at 25 C (18 C then shifted to 25 C for the basement membrane assay); wing phenotype scored in more than 50 flies
• Exposure: Transgenic over-expression of the Drosophila FMR gene (dFMR) driven by Ptc-Gal4 or Vg-Gal4, alone or together with activated RasV12 in MARCM clones; no chemical or fiber exposure
• Main results:
  • Ptc-Gal4-driven dFMR over-expression reduced the wing tissue between longitudinal veins 3 and 4 in more than 50 flies with complete penetrance; Vg-Gal4-driven over-expression produced wing notches
  • In wing discs carrying the puc-lacZ JNK reporter, dFMR over-expression along the anterior-posterior border increased reporter expression, interpreted as JNK pathway up-regulation
  • dFMR over-expressing discs showed MMP1 up-regulation and the labelled cells moved out of the Ptc-Gal4 domain into the posterior compartment; control discs expressing only GFP showed no MMP expression
  • dFMR over-expression produced modest, incompletely penetrant basement membrane degradation, mainly in the hinge region of the wing disc
  • In clones co-expressing dFMR and RasV12, no over-proliferation or migration of tumour tissue to contiguous organs was seen compared with RasV12-only controls (data not shown)
• The authors' conclusion: The author concluded that the data provide a link between FMR and the JNK pathway and suggest FMR may contribute to MPM tumorigenesis via JNK up-regulation, MMP up-regulation and basement membrane degradation, while stating this connection is speculative; dFMR and RasV12 did not collaborate, and cooperation with NF2 mutations was proposed for future study
• Limitations the authors state:
  • The author states the proposed contribution of FMR to MPM tumorigenesis is speculative and unverified experimentally
  • The author states it is unknown whether FMR up-regulates JNK directly or indirectly, and that non-JNK mechanisms cannot be excluded
  • The basement membrane degradation was incompletely penetrant, possibly because of variable transgene expression

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Prognosis, Carcinogenesis, Metastasis.

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