Aljabban Jihad, Syed Saad, Syed Sharjeel, Rohr Michael, Weisleder Noah, McElhanon Kevin E, Hasan Laith, Safeer Laraib, Hoffman Kalyn, Aljabban Nabeal, Mukhtar Mohamed, Adapa Nikhil, Allarakhia Zahir, Panahiazar Maryam, Neuhaus Isaac, Kim Susan, Hadley Dexter, Jarjour Wael
University of Wisconsin Hospital and Clinics, Madison, WI, USA.
Stanford University School of Medicine, Palo Alto, CA, USA.
Heliyon. 2020 Sep 24;6(9):e04866. doi: 10.1016/j.heliyon.2020.e04866. eCollection 2020 Sep.
Dermatomyositis (DM) is a progressive, idiopathic inflammatory myopathy with poorly understood pathogenesis. A hallmark of DM is an increased risk for developing breast, ovarian, and lung cancer. Since autoantibodies against anti-TIF-1-γ, a member of the tripartite motif (TRIM) proteins, has a strong association with malignancy, we examined expression of the TRIM gene family to identify pathways that may be contributing to DM pathogenesis.
We employed the Search Tag Analyze Resource for GEO platform to search the NCBI Gene Expression Omnibus to elucidate TRIM family gene expression as well as oncogenic drivers in DM pathology. We conducted meta-analysis of the data from human skin (60 DM vs 34 healthy) and muscle (71 DM vs 22 healthy).
We identified genes involved in innate immunity, antigen presentation, metabolism, and other cellular processes as facilitators of DM disease activity and confirmed previous observations regarding the presence of a robust interferon signature. Moreover, analysis of DM muscle samples revealed upregulation of TRIM14, TRIM22, TRIM25, TRIM27, and TRIM38. Likewise, analysis of DM skin samples showed upregulation of TRIM5, TRIM6, TRIM 14, TRIM21, TRIM34, and TRIM38 and downregulation of TRIM73. Additionally, we noted upregulation of oncogenes IGLC1, IFI44, POSTN, MYC, NPM1, and IDO1 and related this change to interferon signaling. While the clinical data associated with genetic data that was analyzed did not contain clinical data regarding malignancy in these cohorts, the observed genetic changes may be associated with homeostatic and signaling changes that relate to the increased risk in malignancy in DM.
Our results implicate previously unknown genes as potential drivers of DM pathology and suggest certain TRIM family members may have disease-specific roles with potential diagnostic and therapeutic implications.
皮肌炎（DM）是一种进行性、特发性炎性肌病，其发病机制尚不清楚。DM的一个标志是患乳腺癌、卵巢癌和肺癌的风险增加。由于针对三方基序（TRIM）蛋白成员抗TIF-1-γ的自身抗体与恶性肿瘤密切相关，我们研究了TRIM基因家族的表达，以确定可能导致DM发病机制的途径。
我们利用GEO平台的搜索标签分析资源，在NCBI基因表达综合数据库中搜索，以阐明TRIM家族基因表达以及DM病理学中的致癌驱动因素。我们对来自人类皮肤（60例DM患者与34例健康对照）和肌肉（71例DM患者与22例健康对照）的数据进行了荟萃分析。
我们确定参与先天免疫、抗原呈递、代谢和其他细胞过程的基因是DM疾病活动的促进因素，并证实了先前关于存在强大干扰素特征的观察结果。此外，对DM肌肉样本的分析显示TRIM14、TRIM22、TRIM25、TRIM27和TRIM38上调。同样，对DM皮肤样本的分析显示TRIM5、TRIM6、TRIM14、TRIM21、TRIM34和TRIM38上调，TRIM73下调。此外，我们注意到癌基因IGLC1、IFI44、POSTN、MYC、NPM1和IDO1上调，并将这种变化与干扰素信号传导相关联。虽然分析的遗传数据相关的临床数据不包含这些队列中关于恶性肿瘤的临床数据，但观察到的基因变化可能与体内平衡和信号变化有关，这些变化与DM中恶性肿瘤风险增加有关。
我们的结果表明，以前未知的基因可能是DM病理学的潜在驱动因素，并表明某些TRIM家族成员可能具有疾病特异性作用，具有潜在的诊断和治疗意义。
