Impact of BSG/CD147 gene expression on diagnostic, prognostic and therapeutic strategies towards malignant cancers and possible susceptibility to SARS-CoV-2.

BACKGROUND: 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. METHODS: 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 (m62A) and 5'-uridylic acid (UMP) on BSG expression were also conducted. RESULTS: 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, m62A or UMP in cancer cell lines, suggesting therapeutic potentials for interfering entry of SARS-CoV-2. CONCLUSIONS: 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, m62A and UMP imply therapeutic potentials in interfering with entry of SARS-CoV-2 and progression of malignant cancers.

Cyclophilin A/CD147 Interaction: A Promising Target for Anticancer Therapy.

Cyclophilin A (CypA), which has peptidyl-prolyl cis-trans isomerase (PPIase) activity, regulates multiple functions of cells by binding to its extracellular receptor CD147. The CypA/CD147 interaction plays a crucial role in the progression of several diseases, including inflammatory diseases, coronavirus infection, and cancer, by activating CD147-mediated intracellular downstream signaling pathways. Many studies have identified CypA and CD147 as potential therapeutic targets for cancer. Their overexpression promotes growth, metastasis, therapeutic resistance, and the stem-like properties of cancer cells and is related to the poor prognosis of patients with cancer. This review aims to understand the biology and interaction of CypA and CD147 and to review the roles of the CypA/CD147 interaction in cancer pathology and the therapeutic potential of targeting the CypA/CD147 axis. To validate the clinical significance of the CypA/CD147 interaction, we analyzed the expression levels of PPIA and BSG genes encoding CypA and CD147, respectively, in a wide range of tumor types using The Cancer Genome Atlas (TCGA) database. We observed a significant association between PPIA/BSG overexpression and poor prognosis, such as a low survival rate and high cancer stage, in several tumor types. Furthermore, the expression of PPIA and BSG was positively correlated in many cancers. Therefore, this review supports the hypothesis that targeting the CypA/CD147 interaction may improve treatment outcomes for patients with cancer.

Development of a novel human CD147 knock-in NSG mouse model to test SARS-CoV-2 viral infection.

BACKGROUND: An animal model that can mimic the SARS-CoV-2 infection in humans is critical to understanding the rapidly evolving SARS-CoV-2 virus and for development of prophylactic and therapeutic strategies to combat emerging mutants. Studies show that the spike proteins of SARS-CoV and SARS-CoV-2 bind to human angiotensin-converting enzyme 2 (hACE2, a well-recognized, functional receptor for SARS-CoV and SARS-CoV-2) to mediate viral entry. Several hACE2 transgenic (hACE2Tg) mouse models are being widely used, which are clearly invaluable. However, the hACE2Tg mouse model cannot fully explain: (1) low expression of ACE2 observed in human lung and heart, but lung or heart failure occurs frequently in severe COVID-19 patients; (2) low expression of ACE2 on immune cells, but lymphocytopenia occurs frequently in COVID-19 patients; and (3) hACE2Tg mice do not mimic the natural course of SARS-CoV-2 infection in humans. Moreover, one of most outstanding features of coronavirus infection is the diversity of receptor usage, which includes the newly proposed human CD147 (hCD147) as a possible co-receptor for SARS-CoV-2 entry. It is still debatable whether CD147 can serve as a functional receptor for SARS-CoV-2 infection or entry. RESULTS: Here we successfully generated a hCD147 knock-in mouse model (hCD147KI) in the NOD-scid IL2Rgammanull (NSG) background. In this hCD147KI-NSG mouse model, the hCD147 genetic sequence was placed downstream of the endogenous mouse promoter for mouse CD147 (mCD147), which creates an in vivo model that may better recapitulate physiological expression of hCD147 proteins at the molecular level compared to the existing and well-studied K18-hACE2-B6 (JAX) model. In addition, the hCD147KI-NSG mouse model allows further study of SARS-CoV-2 in the immunodeficiency condition which may assist our understanding of this virus in the context of high-risk populations in immunosuppressed states. Our data show (1) the human CD147 protein is expressed in various organs (including bronchiolar epithelial cells) in hCD147KI-NSG mice by immunohistochemical staining and flow cytometry; (2) hCD147KI-NSG mice are marginally sensitive to SARS-CoV-2 infection compared to WT-NSG littermates characterized by increased viral copies by qRT-PCR and moderate body weight decline compared to baseline; (3) a significant increase in leukocytes in the lungs of hCD147KI-NSG mice, compared to infected WT-NSG mice. CONCLUSIONS: hCD147KI-NSG mice are more sensitive to COVID-19 infection compared to WT-NSG mice. The hCD147KI-NSG mouse model can serve as an additional animal model for further interrogation whether CD147 serve as an independent functional receptor or accessory receptor for SARS-CoV-2 entry and immune responses.

SARS-CoV-2 Employ BSG/CD147 and ACE2 Receptors to Directly Infect Human Induced Pluripotent Stem Cell-Derived Kidney Podocytes.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the Coronavirus disease 2019 (COVID-19), which has resulted in over 5.9 million deaths worldwide. While cells in the respiratory system are the initial target of SARS-CoV-2, there is mounting evidence that COVID-19 is a multi-organ disease. Still, the direct affinity of SARS-CoV-2 for cells in other organs such as the kidneys, which are often targeted in severe COVID-19, remains poorly understood. We employed a human induced pluripotent stem (iPS) cell-derived model to investigate the affinity of SARS-CoV-2 for kidney glomerular podocytes, and examined the expression of host factors for binding and processing of the virus. We studied cellular uptake of the live SARS-CoV-2 virus as well as a pseudotyped virus. Infection of podocytes with live SARS-CoV-2 or spike-pseudotyped lentiviral particles revealed cellular uptake even at low multiplicity of infection (MOI) of 0.01. We found that direct infection of human iPS cell-derived podocytes by SARS-CoV-2 virus can cause cell death and podocyte foot process retraction, a hallmark of podocytopathies and progressive glomerular diseases including collapsing glomerulopathy observed in patients with severe COVID-19 disease. We identified BSG/CD147 and ACE2 receptors as key mediators of spike binding activity in human iPS cell-derived podocytes. These results show that SARS-CoV-2 can infect kidney glomerular podocytes in vitro via multiple binding interactions and partners, which may underlie the high affinity of SARS-CoV-2 for kidney tissues. This stem cell-derived model is potentially useful for kidney-specific antiviral drug screening and mechanistic studies of COVID-19 organotropism.

SARS-CoV-2 host receptors ACE2 and CD147 (BSG) are present on human oocytes and blastocysts.

PURPOSE: To visualize SARS-CoV-2 host receptors ACE2 and CD147 on human oocytes and blastocysts. METHODS: Immunohistochemistry and confocal microscopy on human primary oocytes and pre (5 days post fertilization (dpf5) and (dpf6))- and peri (dpf7)-implantation blastocysts donated to research. RESULTS: SARS-CoV-2 host receptors ACE2 and CD147 are present on the membrane of trophectoderm, epiblast and hypoblast cells in human blastocysts. CD147 is also present on the oolemma. CONCLUSION: Theoretically, the earliest stages of embryonic development may be vulnerable for SARS-CoV-2 infection.

Integrated Bioinformatic Analysis of SARS-CoV-2 Infection Related Genes ACE2, BSG and TMPRSS2 in Aerodigestive Cancers.

BACKGROUND: Cancer patients are more vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection than the general population, with lung epithelial cells or enterocytes being the main targets. However, the expressions of SARS-CoV-2 entry-related genes in aerodigestive cancers have not been fully elucidated. METHODS: In this study, the expressions of SARS-CoV-2 receptors and cofactors, including angiotensin I-converting enzyme 2 (ACE2), basigin (BSG) and transmembrane serine protease 2 (TMPRSS2), were comprehensively assessed. We compared BSG and TMPRSS2 expressions between aerodigestive cancers and matched normal tissues through Gene Expression Profiling Interactive Analysis 2 (GEPIA2). Furthermore, expressions in healthy colon tissues at different anatomical locations were explored using the Genotype-Tissue Expression (GTEx) dataset. In addition, expressions among different tumor stages and the prognostic values were detected through GEPIA2. Moreover, the correlation between gene expression and immune infiltration was explored via Tumor Immune Estimation Resource (TIMER). Finally, expressions in primary colorectal cancer (CRC), lung metastasis and liver metastasis were investigated using the Gene Expression Omnibus (GEO) dataset GSE41258. RESULTS: Similar to ACE2, TMPRSS2 and BSG were also highly expressed in the digestive tracts. Intriguingly, BSG/TMPRSS2 expression in adjacent normal colon tissue or lung tissue was higher than that in corresponding healthy tissue, whereas they varied not among different tumor stages and correlated not with prognosis in aerodigestive cancers. Moreover, ACE2 was expressed at higher levels in lung metastases from CRC than in normal lung tissues. CONCLUSION: SARS-CoV-2 entry genes were highly expressed in CRC, and we reported for the first time higher expression of ACE2 in lung metastases from CRC than in normal lung, indicating that these patients may be more susceptible to extrapulmonary or pulmonary SARS-CoV-2 infection. Since our study is a bioinformatic analysis, further experimental evidences and clinical data are urgently needed.

Cardiorenal Tissues Express SARS-CoV-2 Entry Genes and Basigin (BSG/CD147) Increases With Age in Endothelial Cells.

Vascular and cardiovascular inflammation and thrombosis occur in patients with severe coronavirus disease-2019 (COVID-19). Advancing age is the most significant risk factor for severe COVID-19. Using transcriptomic databases, the authors found that: 1) cardiovascular tissues and endothelial cells express putative genes for severe acute respiratory syndrome coronavirus-2 infection, including angiotensin-converting enzyme 2 (ACE2) and basigin (BSG); 2) severe acute respiratory syndrome coronavirus-2 receptor pathways ACE2/transmembrane serine protease 2 and BSG/peptidylprolyl isomerase B(A) polarize to lung/epithelium and vessel/endothelium, respectively; 3) expression of host genes is relatively stable with age; and 4) notable exceptions are ACE2, which decreases with age in some tissues, and BSG, which increases with age in endothelial cells, suggesting that BSG expression in the vasculature may explain the heightened risk for severe disease with age.

Eyes on coronavirus.

Recently, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has spread around the world and is receiving worldwide attention. Approximately 20% of infected patients are suffering from severe disease of multiple systems and in danger of death, while the ocular complications of SARS-CoV-2-infected patients have not been reported generally. Herein, we focus on two major receptors of SARS-CoV-2, ACE2 and CD147 (BSG), in human ocular cells, and interpret the potential roles of coronaviruses in human ocular tissues and diseases.

Structural Variability, Expression Profile, and Pharmacogenetic Properties of TMPRSS2 Gene as a Potential Target for COVID-19 Therapy.

The human serine protease serine 2 TMPRSS2 is involved in the priming of proteins of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and represents a possible target for COVID-19 therapy. The TMPRSS2 gene may be co-expressed with SARS-CoV-2 cell receptor genes angiotensin-converting enzyme 2 (ACE2) and Basigin (BSG), but only TMPRSS2 demonstrates tissue-specific expression in alveolar cells according to single-cell RNA sequencing data. Our analysis of the structural variability of the TMPRSS2 gene based on genome-wide data from 76 human populations demonstrates that a functionally significant missense mutation in exon 6/7 in the TMPRSS2 gene is found in many human populations at relatively high frequencies, with region-specific distribution patterns. The frequency of the missense mutation encoded by rs12329760, which has previously been found to be associated with prostate cancer, ranged between 10% and 63% and was significantly higher in populations of Asian origin compared with European populations. In addition to single-nucleotide polymorphisms, two copy number variants were detected in the TMPRSS2 gene. A number of microRNAs have been predicted to regulate TMPRSS2 and BSG expression levels, but none of them is enriched in lung or respiratory tract cells. Several well-studied drugs can downregulate the expression of TMPRSS2 in human cells, including acetaminophen (paracetamol) and curcumin. Thus, the interactions of TMPRSS2 with SARS-CoV-2, together with its structural variability, gene-gene interactions, expression regulation profiles, and pharmacogenomic properties, characterize this gene as a potential target for COVID-19 therapy.

Human Oocytes Express Both ACE2 and BSG Genes and Corresponding Proteins: Is SARS-CoV-2 Infection Possible?

In addition to a number of scientific and medical questions about SARS-CoV-2 infection that still need to be answered, there is also the question of how this highly virulent virus and COVID-19 disease affect gametogenesis in humans. Even more important is the question of whether the virus can also enter and infect oocytes and possibly alter them in an unknown way, which could also affect the development and status of the human embryo. The answers to these questions are still poorly known, so we reviewed the human oocyte transcriptome and proteome obtained in our previous studies and found that human oocytes from the in vitro fertilization program expressed both the ACE2 and BSG genes and the corresponding ACE2 and BSG proteins. This means that human oocytes possess the molecular 'machinery' to facilitate SARS-CoV-2 entrance and infection. According to various studies, especially in animal models, different viruses can infect oocytes, so infection of the oocyte with SARS-Cov-2 cannot be completely ruled out. A hypothetical model of human oocyte infection with this virus has been proposed.

Safety in Endoscopy for Patients and Healthcare Workers During the COVID-19 Pandemic.

The coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is still wreaking havoc in many parts of the world and poses a great burden to healthcare systems worldwide. Mitigation and suppression strategies have been implemented globally but the disease has proven to be difficult to contain. Initially many elective gastrointestinal endoscopies were cancelled to reduce the risk of infection and conserve personal protective equipment, but many endoscopy units are now faced with the dilemma of resuming endoscopy service during the pandemic as indefinitely postponing diagnostic procedures may lead to a delay in the diagnosis and treatment of malignancies. Further concerns are surfacing as COVID-19 is now known to affect the gastrointestinal tract and may potentially be spread via the fecal-oral route. Until more effective drugs and vaccines are available, it is unlikely that the pandemic will wind down in the near future. Maintaining a balance between protecting healthcare workers and patients from being infected on the one hand and providing timely and effective clinical care on the other will become increasingly important as the pandemic persists. In this narrative review, the risk of COVID-19 infection for healthcare workers and patients undergoing endoscopy, and recommendations on maintaining safe, high-quality endoscopy practice will be discussed.