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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治疗方法的候选靶点。

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

机构信息

Department of Biology, University of Pisa, Pisa, Italy.

Department of Pathology, Rigshospitalet, University of Copenhagen, 2100, Copenhagen, Denmark.

出版信息

Cancer Gene Ther. 2024 Nov;31(11):1708-1720. doi: 10.1038/s41417-024-00805-4. Epub 2024 Sep 12.

DOI:10.1038/s41417-024-00805-4
PMID:39300217
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11567880/
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.

摘要

恶性胸膜间皮瘤 (MPM) 是一种预后不良的侵袭性癌症，迫切需要确定新的可用药靶标。在之前的工作中，我们鉴定了 15 个在 MPM 组织中高度表达且与预后不良相关的失调基因。在这里，我们在 211 名 MPM 患者的独立数据集 (EGA, EGAD00001001915) 和 MPM 细胞系面板上验证了这些发现。此外，我们进行了体外基因沉默，随后进行了增殖、细胞毒性、半胱天冬酶和迁移测定，以确定这些靶标是否可以作为癌症驱动基因。最终确定了三个新的候选基因（即 BAG2、MAD2L1 和 MDK），它们编码的蛋白可以作为可用药靶标。此外，值得注意的是，对组织进行的免疫组织化学分析表明，BAG2 和 MAD2L1 的过表达可以将 MPM 与 RMP 患者区分开来。此外，当我们测试 Neratinib（MAD2L1 的抑制剂）和 iMDK（MDK 的抑制剂）时，我们发现它们对 MPM 细胞有效，部分表型类似于 MAD2L1 和 MDK 基因沉默的作用。总之，在本工作中，我们报告 BAG2、MAD2L1 和 MDK 是 MPM 的真正癌症驱动基因，值得进一步研究。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8489/11567880/bf10440089a2/41417_2024_805_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8489/11567880/c18782ad66a3/41417_2024_805_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8489/11567880/e3338a8bedb4/41417_2024_805_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8489/11567880/b5f45ed1c849/41417_2024_805_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8489/11567880/c110bb1eb9be/41417_2024_805_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8489/11567880/c0efb8ee81ce/41417_2024_805_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8489/11567880/ba397a9288cf/41417_2024_805_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8489/11567880/729eace8ce51/41417_2024_805_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8489/11567880/bf10440089a2/41417_2024_805_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8489/11567880/c18782ad66a3/41417_2024_805_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8489/11567880/e3338a8bedb4/41417_2024_805_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8489/11567880/b5f45ed1c849/41417_2024_805_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8489/11567880/c110bb1eb9be/41417_2024_805_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8489/11567880/c0efb8ee81ce/41417_2024_805_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8489/11567880/ba397a9288cf/41417_2024_805_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8489/11567880/729eace8ce51/41417_2024_805_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8489/11567880/bf10440089a2/41417_2024_805_Fig8_HTML.jpg

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