AXL Inactivation Inhibits Mesothelioma Growth and Migration via Regulation of p53 Expression

Our plain-English summary of AXL Inactivation Inhibits Mesothelioma Growth and Migration via Regulation of p53 Expression, by W. Song, H. Wang, M. Lu, et al (Cancers, 2020).

The study

• Authors: W. Song, H. Wang, M. Lu, X. Ni, N. Bahri, S. Zhu, L. Chen, Y. Wu, J. Qiu, J.A. Fletcher, W.B. Ou
• Journal: Cancers
• Published: 2020;12(10)
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma is a locally aggressive and highly lethal neoplasm. Dysregulation and activation of Gas6/AXL tyrosine kinase signaling are associated with mesothelioma progression, but the mechanisms of these AXL tumorigenic roles are poorly understood. p53 mutants in lung carcinoma upregulate AXL expression by binding and acetylating the AXL promoter. Although TP53 mutations are uncommon in mesothelioma, we hypothesized that these tumors might have alternative feedback mechanisms between AXL and p53. In the current report, we investigated AXL regulation of TP53 transcription, expression, and biological function in mesothelioma. AXL expression was stronger in mesothelioma than most of the other tumor types from the TCGA gene expression profile dataset. AXL knockdown by shRNA induced wild-type and mutant p53 expression in mesothelioma cell lines, suggesting that AXL pro-tumorigenic roles result in part from the suppression of p53 function. Likewise, induced AXL inhibited expression of wild type p53 in COS-7 cells and 293T cells. Immunofluorescence staining showed nuclear colocalization of AXL and p53; however, association of AXL and p53 was not demonstrated in immunoprecipitation complexes. The AXL effects on p53 expression resulted from the inhibition of TP53 transcription, as demonstrated by qRT-PCR after AXL silencing and TP53 promotor dual luciferase activity assays. Chromatin immunoprecipitation-qPCR and sequencing showed that AXL bound to the initial 600 bp sequence at the 5' end of the TP53 promoter. AXL inhibition (shRNA or R428) reduced mesothelioma cell viability, migration, and invasion, whereas TP53 shRNA knockdown attenuated antiproliferative, migration, and invasive effects of AXL silencing or AXL inactivation in these cells. These studies demonstrate a novel feedback regulation loop between AXL and p53, and provide a rationale for mesothelioma therapies targeting AXL/p53 signaling.

In plain English

This was a laboratory study of mesothelioma cell lines combined with analysis of published TCGA expression data; asbestos appears only in the authors' description of mesothelioma as an asbestos-associated cancer, and no exposure was measured. Using TCGA data from 87 mesothelioma patients, the authors reported that AXL expression was stronger in mesothelioma than most other cancer types and that high AXL expression correlated with reduced overall survival (p less than 0.0001), with similar correlations in biphasic (p = 0.0023) and epithelioid (p = 0.0032) subtypes. In cell lines, shRNA silencing of AXL (more than 90% inhibition at 96 hours) raised p53 and p21 protein in three wild-type TP53 lines (MESO924, MESO296, MESO428) and mildly in the TP53-mutant line JMN1B, and raised TP53 transcripts. AXL overexpression lowered p53 in COS-7 and 293T cells and reduced TP53 promoter activity by 40%; chromatin immunoprecipitation placed AXL binding in the first roughly 600 bp of the TP53 promoter. In MESO924, AXL shRNA or R428 cut viability about 30% at day 3 and slowed migration; R428 reduced invasion; TP53 knockdown attenuated these effects.

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 study in mesothelioma cell lines (shRNA knockdown, transfection, immunoprecipitation, ChIP, luciferase, viability/migration/invasion assays) together with analysis of published TCGA mesothelioma expression data
• Who was studied: Published TCGA expression/survival data from 87 mesothelioma patients; human mesothelioma cell lines (including MESO924, MESO296, MESO428, MESO257, MESO507, JMN1B), eight frozen clinical mesothelioma tissue samples from Brigham and Women's Hospital, plus COS-7 and 293T cells
• Exposure: No asbestos or other environmental exposure was studied; the laboratory interventions were lentiviral AXL or p53 shRNA knockdown, AXL/TP53 expression constructs, and the AXL inhibitor R428 (1 µM). Mesothelioma is described by the authors as an asbestos-associated cancer.
• Main results:
  • In the TCGA dataset, high AXL expression in mesothelioma was correlated with reduced overall survival (p < 0.0001); about 24.7% of patients were in the AXL high expression group
  • By histologic subtype, higher AXL expression correlated with poorer overall survival in biphasic (p = 0.0023) and epithelioid (p = 0.0032) mesotheliomas
  • AXL shRNA (more than 90% knockdown at 96 h) upregulated p53 and p21 in the three wild-type p53 lines and gave a mild increase in the p53-mutant line JMN1B
  • No AXL-p53 protein complex was detected by immunoprecipitation in MESO924, MESO257 and MESO428
  • AXL and p53 colocalized in the nucleus by cell fraction immunoblotting and immunofluorescence
  • TP53 transcripts rose after AXL knockdown, and AXL reduced TP53 promoter activity by 40% in dual-luciferase assays
  • ChIP in MESO924 localized AXL binding to the first approximately 600 bp at the 5' end of the TP53 promoter
  • AXL knockdown or R428 reduced MESO924 cell viability by about 30% at day 3; p53 knockdown decreased this antiproliferative effect
  • In MESO924, R428 (1 µM) or AXL shRNA inhibited migration (wound closure), and p53 shRNA knockdown attenuated the antimigration effect
  • In MESO924 invasion assays, R428 (the only AXL intervention tested for invasion) inhibited invasiveness, and p53 shRNA knockdown attenuated this effect
• The authors' conclusion: The authors concluded that AXL negatively regulates p53 by binding the TP53 promoter and inhibiting TP53 transcription, that AXL mediates mesothelioma cell growth through AXL/p53 signaling, and that targeting this axis could be a useful treatment strategy
• Limitations the authors state:
  • Too few TCGA cases of sarcomatoid or diffuse malignant mesothelioma for prognostic analysis in those subgroups
  • AXL and TP53 transcript levels in the TCGA mesothelioma series showed no clear correlation
  • The authors state that the nuclear localization of AXL and its exact binding site in the TP53 promoter remain to be worked out in future experiments

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Neoplasm, Carcinoma.

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