BAG2, MAD2L1, and MDK are cancer-driver genes and candidate targets for novel therapies in malignant pleural mesothelioma

IF 4.8 3区医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Cancer gene therapy Pub Date : 2024-09-12 DOI:10.1038/s41417-024-00805-4

Luisa Bisceglia, Federica Morani, Lara Guerrieri, Eric Santoni-Rugiu, Pınar Çakılkaya, Cristian Scatena, Rosa Scarpitta, Lars H. Engelholm, Niels Behrendt, Federica Gemignani, Stefano Landi

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Abstract

Malignant pleural mesothelioma (MPM) is an aggressive cancer with a poor prognosis and the identification of novel druggable targets is urgently needed. In previous work, we identified 15 deregulated genes highly expressed in MPM tissues and correlated with a poor prognosis. Here, we validated these findings on an independent dataset of 211 MPM patients (EGA, EGAD00001001915) and on a panel of MPM cell lines. Furthermore, we carried out in vitro gene silencing followed by proliferation, cytotoxicity, caspase, and migration assays to define whether these targets could be cancer-driver genes. We ended up with three novel candidates (i.e., BAG2, MAD2L1, and MDK), whose encoded proteins could be exploited as druggable targets. Moreover, of novelty, immunohistochemistry analysis on tissues revealed that the overexpression of BAG2 and MAD2L1 could differentiate MPM from RMP patients. Furthermore, when we tested Neratinib (an inhibitor of MAD2L1) and iMDK (an inhibitor of MDK) we found that they are effective on MPM cells, in part phenocopying the effects of MAD2L1 and MDK gene silencing. In summary, in the present work, we report that BAG2, MAD2L1, and MDK are bona fide cancer-driver genes for MPM worth of further studies.

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BAG2、MAD2L1 和 MDK 是癌症驱动基因，也是恶性胸膜间皮瘤新型疗法的候选靶点。

恶性胸膜间皮瘤（MPM）是一种侵袭性癌症，预后较差，因此急需确定新的药物靶点。在之前的研究中，我们发现了 15 个在 MPM 组织中高表达的失调基因，这些基因与不良预后相关。在此，我们在 211 名 MPM 患者（EGA，EGAD00001001915）的独立数据集和 MPM 细胞系面板上验证了这些发现。此外，我们还进行了体外基因沉默以及增殖、细胞毒性、caspase 和迁移试验，以确定这些靶点是否可能是癌症驱动基因。最终，我们发现了三个新的候选靶点（即 BAG2、MAD2L1 和 MDK），其编码蛋白可作为药物靶点加以利用。此外，新颖的是，组织免疫组化分析表明，BAG2 和 MAD2L1 的过表达可将 MPM 患者与 RMP 患者区分开来。此外，当我们测试奈拉替尼（MAD2L1 的抑制剂）和 iMDK（MDK 的抑制剂）时，发现它们对 MPM 细胞有效，在一定程度上复制了 MAD2L1 和 MDK 基因沉默的效果。总之，在本研究中，我们发现 BAG2、MAD2L1 和 MDK 是 MPM 的真正致癌基因，值得进一步研究。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer gene therapy 医学-生物工程与应用微生物

CiteScore

10.20

自引率

0.00%

发文量

150

审稿时长

4-8 weeks

期刊介绍： Cancer Gene Therapy is the essential gene and cellular therapy resource for cancer researchers and clinicians, keeping readers up to date with the latest developments in gene and cellular therapies for cancer. The journal publishes original laboratory and clinical research papers, case reports and review articles. Publication topics include RNAi approaches, drug resistance, hematopoietic progenitor cell gene transfer, cancer stem cells, cellular therapies, homologous recombination, ribozyme technology, antisense technology, tumor immunotherapy and tumor suppressors, translational research, cancer therapy, gene delivery systems (viral and non-viral), anti-gene therapy (antisense, siRNA & ribozymes), apoptosis; mechanisms and therapies, vaccine development, immunology and immunotherapy, DNA synthesis and repair. Cancer Gene Therapy publishes the results of laboratory investigations, preclinical studies, and clinical trials in the field of gene transfer/gene therapy and cellular therapies as applied to cancer research. Types of articles published include original research articles; case reports; brief communications; review articles in the main fields of drug resistance/sensitivity, gene therapy, cellular therapy, tumor suppressor and anti-oncogene therapy, cytokine/tumor immunotherapy, etc.; industry perspectives; and letters to the editor.