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HORMAD1 是肺腺癌的一个负性预后指标，并特异性决定其对氧化应激和遗传毒性应激的抵抗能力。

HORMAD1 Is a Negative Prognostic Indicator in Lung Adenocarcinoma and Specifies Resistance to Oxidative and Genotoxic Stress.

机构信息

Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.

Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas.

出版信息

Cancer Res. 2018 Nov 1;78(21):6196-6208. doi: 10.1158/0008-5472.CAN-18-1377. Epub 2018 Sep 5.

DOI:10.1158/0008-5472.CAN-18-1377
PMID:30185546
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6440700/
Abstract

Cancer testis antigens (CTA) are expressed in testis and placenta and anomalously activated in a variety of tumors. The mechanistic contribution of CTAs to neoplastic phenotypes remains largely unknown. Using a chemigenomics approach, we find that the CTA HORMAD1 correlates with resistance to the mitochondrial complex I inhibitor piericidin A in non-small cell lung cancer (NSCLC). Resistance was due to a reductive intracellular environment that attenuated the accumulation of free radicals. In human lung adenocarcinoma (LUAD) tumors, patients expressing high HORMAD1 exhibited elevated mutational burden and reduced survival. HORMAD1 tumors were enriched for genes essential for homologous recombination (HR), and HORMAD1 promoted RAD51-filament formation, but not DNA resection, during HR. Accordingly, HORMAD1 loss enhanced sensitivity to γ-irradiation and PARP inhibition, and HORMAD1 depletion significantly reduced tumor growth These results suggest that HORMAD1 expression specifies a novel subtype of LUAD, which has adapted to mitigate DNA damage. In this setting, HORMAD1 could represent a direct target for intervention to enhance sensitivity to DNA-damaging agents or as an immunotherapeutic target in patients. This study uses a chemigenomics approach to demonstrate that anomalous expression of the CTA HORMAD1 specifies resistance to oxidative stress and promotes HR to support tumor cell survival in NSCLC. .

摘要

癌症睾丸抗原 (CTA) 在睾丸和胎盘组织中表达，并且在多种肿瘤中异常激活。CTA 对肿瘤表型的机制贡献在很大程度上仍然未知。我们使用化学基因组学方法发现，CTA HORMAD1 与非小细胞肺癌 (NSCLC) 对线粒体复合物 I 抑制剂 piericidin A 的耐药性相关。耐药性是由于还原性的细胞内环境，削弱了自由基的积累。在人类肺腺癌 (LUAD) 肿瘤中，高表达 HORMAD1 的患者表现出更高的突变负担和更低的存活率。HORMAD1 肿瘤富集了同源重组 (HR) 所必需的基因，并且 HORMAD1 在 HR 过程中促进 RAD51 丝形成，但不促进 DNA 切除。因此，HORMAD1 缺失增强了对 γ 辐射和 PARP 抑制的敏感性，并且 HORMAD1 耗竭显著降低了肿瘤生长。这些结果表明，HORMAD1 的表达指定了 LUAD 的一种新型亚型，该亚型已经适应减轻 DNA 损伤。在这种情况下，HORMAD1 可以作为干预的直接靶点，以增强对 DNA 损伤剂的敏感性，或作为免疫治疗靶点用于患者。本研究使用化学基因组学方法证明，CTA HORMAD1 的异常表达指定了对氧化应激的耐药性，并促进 HR 以支持 NSCLC 中的肿瘤细胞存活。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a004/6440700/61efd576eee8/nihms-1008805-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a004/6440700/f7acb5d9f843/nihms-1008805-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a004/6440700/04a079531838/nihms-1008805-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a004/6440700/8641d1edd9c1/nihms-1008805-f0003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a004/6440700/762b3052dd07/nihms-1008805-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a004/6440700/61efd576eee8/nihms-1008805-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a004/6440700/f7acb5d9f843/nihms-1008805-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a004/6440700/04a079531838/nihms-1008805-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a004/6440700/8641d1edd9c1/nihms-1008805-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a004/6440700/519ae84e07a6/nihms-1008805-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a004/6440700/762b3052dd07/nihms-1008805-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a004/6440700/61efd576eee8/nihms-1008805-f0006.jpg

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