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

TL;DR

Cytoplasmic HuR expression in pleural mesothelioma is linked to increased chemoresistance and worse outcomes due to changes in key pathways.

Contribution

The study identifies cytoplasmic HuR as a novel driver of chemoresistance in mesothelioma through CALB2, E2F, and p53 pathways.

Findings

Cytoplasmic HuR expression correlates with worse disease-free survival after chemotherapy.

Forced cytoplasmic HuR increases chemoresistance via CALB2 upregulation and E2F pathway activation.

Cytoplasmic HuR suppresses the p53 pathway, contributing to drug resistance.

Abstract

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.

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.

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.

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.

We found that cytoplasmic HuR expression increases chemoresistance and postoperative risk of recurrence in pleural mesothelioma. It has been suggested that this is due to increased expression of CALB2, up‐regulation of the E2F pathway and suppression of the p53 pathway.

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