Cytoplasmic HuR Expression Enhances Chemoresistance in Pleural Mesothelioma Through Increased Expression of CALB2, Promotion of the E2F Pathway, and Suppression of the p53 Pathway

Our plain-English summary of Cytoplasmic HuR Expression Enhances Chemoresistance in Pleural Mesothelioma Through Increased Expression of CALB2, Promotion of the E2F Pathway, and Suppression of the p53 Pathway, by S. Kirimura, M. Kurata, H. Ishibashi, et al (Thoracic Cancer, 2025).

The study

• Authors: S. Kirimura, M. Kurata, H. Ishibashi, Y. Taniguchi, Y. Kinowaki, K. Sugita, K. Okubo
• Journal: Thoracic Cancer
• Published: 2025;16(7):e70062
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: Chemotherapy is crucial for treating pleural mesothelioma; however, the outcomes are poor, necessitating an urgent need to study the mechanism of chemotherapy resistance in mesothelioma cells. Human antigen R (HuR), an RNA-binding protein and key post-transcriptional regulator of mRNA, is linked to poor prognosis in cancers like mesothelioma. We investigated the involvement of cytoplasmic HuR expression in drug resistance mechanisms in mesothelioma.

Methods: We retrospectively evaluated cytoplasmic HuR expression in 30 patients with pleural mesothelioma who underwent surgical resection using immunohistochemistry. We also examined the role of forced cytoplasmic expression of HuR in drug resistance using mesothelioma cell lines and performed RNA-Seq analysis to identify gene expression changes responsible for drug resistance acquisition via HuR cytoplasmic expression.

Results: Patients with mesotheliomas who expressed cytoplasmic HuR exhibited significantly worse disease-free survival following post-operative chemotherapy. Forced cytoplasmic HuR expression in mesothelioma cell lines increased chemotherapy resistance through increased expression of CALB2, upregulation of the E2F pathway and suppression of the p53 pathway.

Conclusions: Cytoplasmic HuR expression increases the chemoresistance and postoperative recurrence risk of pleural mesothelioma, making it a potential biomarker for predicting therapeutic prognosis. However, the mechanism of HuR transfer to the cytoplasm remains unclear for therapeutic application.

© 2025 The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.

In plain English

This Japanese study combined a retrospective look at tumour samples with laboratory experiments on mesothelioma cells. The authors stained tissue from 30 patients who had surgery for pleural mesothelioma at Tokyo Medical and Dental University Hospital between 2010 and 2017 for a protein called HuR. In 50.0% of patients, HuR appeared in the cytoplasm (the part of the cell outside the nucleus). Reported asbestos exposure did not differ significantly between patients with and without cytoplasmic HuR. Across all patients, overall and disease-free survival did not differ significantly. Among the 20 patients given chemotherapy after surgery, disease-free survival was significantly shorter when cytoplasmic HuR was present (p = 0.0026). In a multivariate analysis the hazard ratio was 5.1854 (95% CI 1.4884 to 18.1137). In one mesothelioma cell line, cells made to carry HuR in the cytoplasm were less affected by cisplatin and pemetrexed. These cells showed more calretinin (the CALB2 gene product), raised E2F-pathway genes and lowered p53-pathway genes. The authors concluded that cytoplasmic HuR increases chemoresistance and recurrence risk and may be a biomarker. They said how HuR moves to the cytoplasm remains 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: Retrospective study of surgical tumour specimens (immunohistochemistry with survival analysis), combined with laboratory experiments on a mesothelioma cell line (forced cytoplasmic HuR expression, drug-sensitivity assays, RNA sequencing, western blotting)
• Who was studied: 30 patients who underwent surgical resection for pleural mesothelioma at Tokyo Medical and Dental University Hospital, Japan, between 2010 and 2017, excluding patients who received chemotherapy before surgery. 20 of them received postoperative chemotherapy. Laboratory work used the ACC-MESO1 mesothelioma cell line.
• Exposure: The factor studied was location of the protein HuR in tumour cells (cytoplasmic versus nuclear). In cell experiments, cells were treated with cisplatin (10 μM) or pemetrexed (50 μM) for 5 days. Asbestos exposure was recorded only as a patient characteristic: 12 of 15 cytoplasmic-HuR-positive and 13 of 15 negative patients were exposed. No fiber type or level of exposure is given.
• Main results:
  • Of the 30 patients, 50.0% showed HuR staining in the tumour cell cytoplasm; the rest showed nuclear staining
  • No significant differences between cytoplasmic-HuR-positive and -negative groups in clinicopathological factors, including asbestos exposure (12 of 15 versus 13 of 15 exposed, p = 1.0000)
  • When all 30 patients were considered, overall survival and disease-free survival did not differ significantly between cytoplasmic-HuR-positive and -negative groups
  • Among patients who received postoperative chemotherapy, disease-free survival was significantly shorter in the cytoplasmic-HuR-positive group (p = 0.0026)
  • In patients who received postoperative chemotherapy (n = 20), necrosis (univariate p = 0.0074) and cytoplasmic HuR correlated with disease-free survival in univariate analysis
  • In multivariate analysis of the same 20 patients, cytoplasmic HuR was the only independent predictor of disease-free survival: hazard ratio 5.1854, 95% CI 1.4884 to 18.1137, p = 0.0099
  • In the mesothelioma cell line, cells engineered to express HuR in the cytoplasm (NES-HuR) showed a significantly smaller drop in proliferative activity under cisplatin and pemetrexed
  • In the same cells, a smaller percentage were killed by chemotherapy, measured by propidium iodide staining
  • RNA sequencing in the engineered cells showed increased mRNA of several drug-resistance genes, including CALB2, LRRC15, LY6K, TAGLN, CNN1, GLIPR1 and PIM1, and upregulation of E2F target genes
  • The p53 pathway gene cluster was downregulated in the engineered cells
  • At the protein level, calretinin increased significantly in the engineered cells
  • PIM1 protein tended to increase in the engineered cells, but not significantly
  • For E2F and p53 themselves, there was no clear trend at the mRNA level and no significant change at the protein level
• The authors' conclusion: The authors concluded that cytoplasmic HuR expression increases chemoresistance and postoperative recurrence risk in pleural mesothelioma, making it a potential biomarker for predicting therapeutic prognosis. In the results section they described the cell-line mechanism (CALB2, E2F, p53) as a hypothesis.
• Limitations the authors state:
  • The study did not identify how HuR moves to the cytoplasm, which the authors said needs further investigation before therapeutic use

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Chemotherapy, Mesothelioma, Prognosis, Surgical Resection, Immunohistochemistry, Disease-Free Survival, Biomarker.

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