HMGB1 as a Key Mediator in Malignant Mesothelioma and a Potential Target for Asbestos-Related Cancer Therapy

Our plain-English summary of HMGB1 as a Key Mediator in Malignant Mesothelioma and a Potential Target for Asbestos-Related Cancer Therapy, by Y.F. Zhong, C. Ding, C.J. Yao, et al (Toxics, 2025).

The study

• Authors: Y.F. Zhong, C. Ding, C.J. Yao, J.C. Wang, M.Q. Feng, X.X. Gong, L. Yu, H.D. Xu, H.L. Xia
• Journal: Toxics
• Published: 2025;13(6)
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is a highly aggressive cancer strongly associated with asbestos exposure, and accumulating evidence suggests that high mobility group box 1 (HMGB1) plays a central role in its pathogenesis. Our in vitro and in vivo experiments revealed that HMGB1 was highly expressed in MM. Both genetic and pharmacological inhibition of HMGB1 markedly suppressed MM cell viability, migration, and invasion, while inducing G1-phase cell cycle arrest and enhancing apoptosis. Interestingly, the inhibition of Toll-like receptor 4 (TLR4), achieved through both siRNA and TAK-242 treatment, not only suppressed tumor-promoting signals but also reduced HMGB1 expression, suggesting a self-amplifying HMGB1-TLR4 loop. Mechanistically, in vitro experiments indicated that suppression of HMGB1 and TLR4 was associated with decreased activation of NF-κB, AKT, and ERK pathways, which are involved in regulating MM cell survival and motility. In xenograft models, treatment with ethyl pyruvate (EP) and TAK-242 significantly suppressed tumor growth and HMGB1 expression, reinforcing their therapeutic potential. Given HMGB1's influence on both tumor cell behavior and the immune microenvironment, targeting the HMGB1-TLR4 axis may not only provide a novel therapeutic strategy for MM but also offer insights into the mechanisms underlying asbestos-induced tumorigenesis, potentially guiding future prevention and intervention strategies in asbestos-exposed populations.

In plain English

This was a laboratory study using cultured cells and mice; no asbestos was used. The authors studied a protein called HMGB1 in two human malignant mesothelioma (MM) cell lines and a normal mesothelial cell line. HMGB1 was significantly higher in the MM cell lines, and plasma HMGB1 was higher in mice carrying MM tumors. Two drugs, ethyl pyruvate (an HMGB1 blocker) and TAK-242 (which blocks HMGB1's receptor, TLR4), reduced MM cell viability. Both drugs, and silencing the HMGB1 gene, reduced migration and invasion. At 10 mM, ethyl pyruvate caused G1-phase arrest, with fewer cells in the DNA-copying S phase; at 20 mM it increased cell death. HMGB1 silencing and TLR4 blocking also increased cell death. Blocking TLR4 also lowered HMGB1. In mice (six per group), both drugs were followed by slower tumor growth and lower tumor weights, though tumor volume differences were not always statistically significant. HMGB1 was significantly reduced in the TAK-242 group. The authors concluded that disrupting this pathway attenuated tumor behaviors in these models. They noted the mice lacked a functional immune system and that long-term effects and toxicities in patients remain unknown.

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: in vitro experiments on cultured cell lines plus an animal experiment (mouse xenograft model)
• Who was studied: The cells were two human malignant mesothelioma cell lines (MSTO-211H and NCI-H2452) and a normal mesothelial cell line (MeT-5A), all bought from ATCC. The animals were female BALB/c nude mice (5 to 6 weeks old) injected with MSTO-211H cells and divided into four groups of 6. The work was done at Hangzhou Medical College, China.
• Exposure: No asbestos exposure was tested. The cells and mice were treated in three ways: siRNA silencing of HMGB1 or TLR4; ethyl pyruvate (an HMGB1 inhibitor), 0 to 20 mM in cells and 100 mg/kg in mice; and TAK-242 (a TLR4 antagonist), 0 to 200 µM in cells and 3 mg/kg in mice.
• Main results:
  • HMGB1 mRNA and protein were significantly higher in the MM cell lines than in the normal mesothelial cells.
  • Plasma HMGB1 was higher in mice bearing MM xenografts than in normal control mice.
  • Ethyl pyruvate and TAK-242 reduced MM cell viability in a dose- and time-dependent way.
  • Ethyl pyruvate significantly suppressed migration and invasion of MM cells.
  • HMGB1 siRNA significantly impaired MM cell migration and invasion compared with control groups.
  • TAK-242 significantly reduced scratch closure rates and the number of invasive cells.
  • TAK-242 (100 and 200 µM) significantly decreased both TLR4 and HMGB1 mRNA levels in MM cells.
  • Ethyl pyruvate at 10 mM caused G1-phase arrest with fewer S-phase cells. Apoptosis rose significantly at 20 mM ethyl pyruvate.
  • HMGB1 silencing significantly increased apoptosis in both MM cell lines.
  • TLR4 inhibition by siRNA or TAK-242 reduced the S-phase population and increased apoptosis.
  • TAK-242 and TLR4 siRNA significantly lowered several downstream signaling molecules in MM cells, including MyD88, NF-κB, ERK and AKT.
  • In xenograft mice, ethyl pyruvate or TAK-242 treatment was followed by slower tumor growth and lower tumor weights than in the PBS-treated model group. Tumor volume differences were not always statistically significant.
  • Tumors from ethyl pyruvate- and TAK-242-treated mice showed lower tumor cell density and more necrosis.
  • Plasma and tumor tissue HMGB1 levels were significantly reduced in the TAK-242-treated mice.
• The authors' conclusion: The authors concluded that disrupting the HMGB1-TLR4 signaling axis, by genetic or drug approaches, significantly attenuated oncogenic behaviors of MM in vitro and in vivo.
• Limitations the authors state:
  • The in vitro models did not fully reproduce the complexity of the tumor microenvironment.
  • The xenograft mice lacked a functional immune system.
  • Long-term effects and possible toxicities of these treatments in clinical settings are unknown.
  • Immune parameters were not directly assessed.

Topics

Medical terms in this study, explained in our Lexicon: High Mobility Group Box 1 (HMGB1), Mesothelioma, Asbestos Exposure, Apoptosis, Carcinogenesis.

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