Huang Zhijian, Gao Yaoxin, Han Yuanyuan, Yang Jingwen, Yang Can, Li Shixiong, Zhou Decong, Huang Qiuyan, Yang Jialiang
Department of Breast Surgical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, China.
Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Biosaf Health. 2023 May 9;5(4):211-26. doi: 10.1016/j.bsheal.2023.05.004.
Recent studies suggested that cancer was a risk factor for coronavirus disease 2019 (COVID-19). Toll-like receptor 7 (TLR7), a severe acute respiratory syndrome 2 (SARS-CoV-2) virus's nucleic acid sensor, was discovered to be aberrantly expressed in many types of cancers. However, its expression pattern across cancers and association with COVID-19 (or its causing virus SARS-CoV-2) has not been systematically studied. In this study, we proposed a computational framework to comprehensively study the roles of TLR7 in COVID-19 and pan-cancers at genetic, gene expression, protein, epigenetic, and single-cell levels. We applied the computational framework in a few databases, including The Cancer Genome Atlas (TCGA), The Genotype-Tissue Expression (GTEx), Cancer Cell Line Encyclopedia (CCLE), Human Protein Atlas (HPA), lung gene expression data of mice infected with SARS-CoV-2, and the like. As a result, TLR7 expression was found to be higher in the lung of mice infected with SARS-CoV-2 than that in the control group. The analysis in the Opentargets database also confirmed the association between TLR7 and COVID-19. There are also a few exciting findings in cancers. First, the most common type of TLR7 was "Missense" at the genomic level. Second, TLR7 mRNA expression was significantly up-regulated in 6 cancer types and down-regulated in 6 cancer types compared to normal tissues, further validated in the HPA database at the protein level. The genes significantly co-expressed with TLR7 were mainly enriched in the toll-like receptor signaling pathway, endolysosome, and signaling pattern recognition receptor activity. In addition, the abnormal TLR7 expression was associated with mismatch repair (MMR), microsatellite instability (MSI), and tumor mutational burden (TMB) in various cancers. Mined by the ESTIMATE algorithm, the expression of TLR7 was also closely linked to various immune infiltration patterns in pan-cancer, and TLR7 was mainly enriched in macrophages, as revealed by single-cell RNA sequencing. Third, abnormal expression of TLR7 could predict the survival of Brain Lower Grade Glioma (LGG), Lung adenocarcinoma (LUAD), Skin Cutaneous Melanoma (SKCM), Stomach adenocarcinoma (STAD), and Testicular Germ Cell Tumors (TGCT) patients, respectively. Finally, TLR7 expressions were very sensitive to a few targeted drugs, such as Alectinib and Imiquimod. In conclusion, TLR7 might be essential in the pathogenesis of COVID-19 and cancers.
近期研究表明，癌症是2019冠状病毒病（COVID-19）的一个风险因素。Toll样受体7（TLR7）是严重急性呼吸综合征冠状病毒2（SARS-CoV-2）病毒的核酸传感器，被发现在多种癌症中异常表达。然而，其在各种癌症中的表达模式以及与COVID-19（或其致病病毒SARS-CoV-2）的关联尚未得到系统研究。在本研究中，我们提出了一个计算框架，以在基因、基因表达、蛋白质、表观遗传和单细胞水平上全面研究TLR7在COVID-19和泛癌中的作用。我们将该计算框架应用于多个数据库，包括癌症基因组图谱（TCGA）、基因型-组织表达（GTEx）、癌细胞系百科全书（CCLE）、人类蛋白质图谱（HPA）、感染SARS-CoV-2的小鼠的肺基因表达数据等。结果发现，感染SARS-CoV-2的小鼠肺中TLR7的表达高于对照组。在OpenTargets数据库中的分析也证实了TLR7与COVID-19之间的关联。在癌症方面也有一些令人兴奋的发现。首先，在基因组水平上，TLR7最常见的类型是“错义”。其次，与正常组织相比，TLR7 mRNA表达在6种癌症类型中显著上调，在6种癌症类型中下调，这在HPA数据库的蛋白质水平上得到了进一步验证。与TLR7显著共表达的基因主要富集在Toll样受体信号通路、内溶酶体和信号模式识别受体活性中。此外，TLR7的异常表达与各种癌症中的错配修复（MMR）、微卫星不稳定性（MSI）和肿瘤突变负担（TMB）相关。通过ESTIMATE算法挖掘发现，TLR7的表达也与泛癌中的各种免疫浸润模式密切相关，单细胞RNA测序显示TLR7主要富集在巨噬细胞中。第三，TLR7的异常表达可以分别预测脑低级别胶质瘤（LGG）、肺腺癌（LUAD）、皮肤黑色素瘤（SKCM）、胃腺癌（STAD）和睾丸生殖细胞肿瘤（TGCT）患者的生存情况。最后，TLR7的表达对一些靶向药物非常敏感，如阿来替尼和咪喹莫特。总之，TLR7可能在COVID-19和癌症的发病机制中至关重要。
