Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, 646000, Sichuan, China.
Basic Medical School, Southwest Medical University, Luzhou, 646000, Sichuan, China.
Mol Biol Rep. 2023 Mar;50(3):2269-2281. doi: 10.1007/s11033-022-08231-1. Epub 2022 Dec 27.
BSG (CD147) is a member of the immunoglobulin superfamily that shows roles for potential prognostics and therapeutics for metastatic cancers and SARS-CoV-2 invasion for COVID-19. The susceptibility of malignant cancers to SARS-CoV-2 as well as the correlations between disease outcome and BSG expression in tumor tissues have not been studied in depth.
In this study, we explored the BSG expression profile, survival correlation, DNA methylation, mutation, diagnostics, prognostics, and tumor-infiltrating lymphocytes (TILs) from different types of cancer tissues with corresponding healthy tissues. In vitro studies for cordycepin (CD), N6-(2-hydroxyethyl) adenosine (HEA), N6, N6-dimethyladenosine (mA) and 5'-uridylic acid (UMP) on BSG expression were also conducted.
We revealed that BSG is conserved among different species, and significantly upregulated in seven tumor types, including ACC, ESCA, KICH, LIHC, PAAD, SKCM and THYM, compared with matched normal tissues, highlighting the susceptibility of these cancer patients to SARS-CoV-2 invasion, COVID-19 severity and progression of malignant cancers. High expression in BSG was significantly correlated with a short OS in LGG, LIHC and OV patients, but a long OS in KIRP patients. Methylation statuses in the BSG promoter were significantly higher in BRCA, HNSC, KIRC, KIRP, LUSC, PAAD, and PRAD tumor tissues, but lower in READ. Four CpGs in the BSG genome were identified as potential DNA methylation biomarkers which could be used to predict malignant cancers from normal individuals. Furthermore, a total of 65 mutation types were found, in which SARC showed the highest mutation frequency (7.84%) and THYM the lowest (0.2%). Surprisingly, both for disease-free and progression-free survival in pan-cancers were significantly reduced after BSG mutations. Additionally, a correlation between BSG expression and immune lymphocytes of CD56bright natural killer cell, CD56dim natural killer cell and monocytes, MHC molecules of HLA-A, HLA-B, HLA-C and TAPBP, immunoinhibitor of PVR, PVRL2, and immunostimulators of TNFRSF14, TNFRSF18, TNFRSF25, and TNFSF9, was revealed in most cancer types. Moreover, BSG expression was downregulated by CD, HEA, mA or UMP in cancer cell lines, suggesting therapeutic potentials for interfering entry of SARS-CoV-2.
Altogether, our study highlights the values of targeting BSG for diagnostic, prognostic and therapeutic strategies to fight malignant cancers and COVID-19. Small molecules CD, HEA, mA and UMP imply therapeutic potentials in interfering with entry of SARS-CoV-2 and progression of malignant cancers.
BSG（CD147）是免疫球蛋白超家族的成员，在转移性癌症的潜在预后和治疗以及 SARS-CoV-2 入侵 COVID-19 方面具有作用。恶性癌症对 SARS-CoV-2 的易感性以及肿瘤组织中疾病结果与 BSG 表达之间的相关性尚未得到深入研究。
在这项研究中，我们从不同类型的癌症组织和相应的正常组织中探讨了 BSG 的表达谱、生存相关性、DNA 甲基化、突变、诊断、预后和肿瘤浸润淋巴细胞（TILs）。我们还进行了关于虫草素（CD）、N6-（2-羟乙基）腺苷（HEA）、N6、N6-二甲基腺苷（mA）和 5'-尿苷酸（UMP）对 BSG 表达的体外研究。
我们揭示了 BSG 在不同物种中是保守的，并且在包括 ACC、ESCA、KICH、LIHC、PAAD、SKCM 和 THYM 在内的七种肿瘤类型中显著上调，与匹配的正常组织相比，这突出了这些癌症患者对 SARS-CoV-2 入侵、COVID-19 严重程度和恶性癌症进展的易感性。BSG 高表达与 LGG、LIHC 和 OV 患者的短 OS 显著相关，但与 KIRP 患者的长 OS 相关。BRCA、HNSC、KIRC、KIRP、LUSC、PAAD 和 PRAD 肿瘤组织中的 BSG 启动子甲基化状态明显较高，而 READ 则较低。BSG 基因组中的四个 CpG 被确定为潜在的 DNA 甲基化生物标志物，可用于从正常人中预测恶性癌症。此外，发现了总共 65 种突变类型，其中 SARC 显示出最高的突变频率（7.84%），而 THYM 显示出最低的突变频率（0.2%）。令人惊讶的是，在 pan-cancers 中，无病和无进展生存期在 BSG 突变后均显著降低。此外，在大多数癌症类型中，BSG 表达与 CD56bright 自然杀伤细胞、CD56dim 自然杀伤细胞和单核细胞、MHC 分子 HLA-A、HLA-B、HLA-C 和 TAPBP、免疫抑制剂 PVR、PVRL2 以及免疫刺激剂 TNFRSF14、TNFRSF18、TNFRSF25 和 TNFSF9 之间存在相关性。此外，在癌细胞系中，CD、HEA、mA 或 UMP 下调了 BSG 的表达，这表明它们具有干扰 SARS-CoV-2 进入的治疗潜力。
总的来说，我们的研究强调了针对 BSG 的靶向治疗在诊断、预后和治疗恶性癌症和 COVID-19 方面的价值。小分子 CD、HEA、mA 和 UMP 暗示在干扰 SARS-CoV-2 进入和恶性癌症进展方面具有治疗潜力。
