CD147 And Cyclophilin A (CyPA) Play Key Roles In COVID-19 Severity, Cancer Progression And Chemotherapy Resistance In Cancer Patients With COVID-19

COVID-19 News: Iranian researchers from Qazvin University of Medical Sciences, Lorestan University of Medical Sciences, Shiraz University of Medical Sciences, University of Tehran and Tehran University of Medical Sciences are claiming that CD147 And Cyclophilin A (CyPA) play key roles in COVID-19 severity, cancer progression and chemotherapy resistance in cancer patients with COVID-19.
 
The ongoing COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has disproportionately affected individuals with pre-existing conditions such as cancer. Patients with cancer are more susceptible to severe COVID-19 infection and increased mortality rates as reported in studies, case reports and COVID-19 News coverages.
 
The Iranian researchers delved into the role of CD147 and CyPA in COVID-19 severity, cancer progression, and chemotherapy resistance in cancer patients with COVID-19.
 
Furthermore, the researchers explored how Hypoxia-inducible Factor-1 alpha (HIF-1α) activation during hypoxic conditions occurring during COVID-19 infection may increase the expression of both CD147 and CyPA, providing a potential therapeutic target for cancer patients during the pandemic.
 
CD147 and CyPA in SARS-CoV-2 Infection
CD147, a transmembrane glycoprotein and part of the immunoglobulin superfamily, is found in various organs and cell types, including T-cells, endothelial cells, and central nervous system (CNS) cells. Studies have shown that CD147 plays a significant role in viral infections, particularly in SARS-CoV-2 infection. CD147 interacts with the SARS-CoV-2-S protein, allowing the virus to penetrate host cells through binding to CD147.
 
CyPA is the most abundant protein in the Cyclophilin family, with roles in intracellular protein synthesis, transportation, folding, signal transduction, and immunosuppression. CyPA is also involved in viral infections, including HIV, HCV, and HBV. Recent studies suggest that the CyPA/CD147 interaction may facilitate SARS-CoV-2 viral entry and replication. Moreover, CyPA expression is upregulated during SARS-CoV-2 infection.
 
The Role of HIF-1α Activation in CD147 and CyPA Expression
Hypoxic conditions, which occur during COVID-19 infection, increase CD147 and CyPA expression through HIF-1α activation. We propose that HIF-1α activation by COVID-19 infection increases the expression of CD147 and CyPA in infected cells and exposed cells to hypoxic conditions. This hypothesis requires further investigation to explore its potential as a therapeutic target for cancer patients with COVID-19.
 
CD147 and CyPA in Cancer Progression and Chemotherapy Resistance
CD147 and CyPA not only contribute to SARS-CoV-2 infection by facilitating viral entry and replication but also play a role in COVID-19-associated cancer progression and chemo-resistance.
 
CD147 is involved in the progression of various cancers, including hematological malignancies and solid tumors, through numerous mechanisms.
 
CD147 is a receptor for CyPA, which causes metastasis through the ERK1/2 signaling pathway and induces matrix metalloproteinases (MMPs) synthesis and cancer progression through the (FAK)-PI3K signaling pathway.
 
CyPA and CD147 are expressed at higher levels in pancreatic cancer tissues, with CD147 antibody significantly inhibiting pancreatic cancer cell proliferation.
 
In cholangiocarcinoma, increased CypA expression is driven by HIF-1α, which triggers the ERK1/2 signaling pathway through interaction with the CD147 receptor, leading to cancer progression.
 
In colorectal cancer, CD147 binds to CD44 via TFF-3 and activates STAT3, which increases PTGS2 and promotes cancer progression. CD147 also binds to the Annexin A2 N-terminal, preventing its phosphorylation with Src and impairing Dock3 expression. The lack of Dock3 expression subsequently causes cancer migration.
 
CD147 also contributes to oncogenic functions such as the production of vascular endothelial growth factor (VEGF) in endothelial cells, facilitating glycolysis, proliferation, invasion, and inhibition of apoptosis in hypoxic conditions.
Moreover, interaction between HE4 and CD147 in ovarian carcinoma promotes invasion and metastasis by forming a protein complex with Annexin A2 as a bridge.
 
High CD147 expression is associated with increased tumorigenic potential and chemo-resistance in vivo. Glioma cells with high CD147 expression exhibit temozolomide (TMZ) resistance, while ovarian cancer tissues exhibit paclitaxel resistance. Inhibition of CD147 expression increases the inhibitory effect of TMZ on cell survival. CD147 is also involved in the reduction of reactive oxygen species (ROS) production, a consequence of TMZ treatment, by stabilizing nuclear factor E2-related factor 2 (Nrf2) through suppression of the GSK3β/β-TrCP-dependent protein.
 
Cancer cells with high levels of CD147 expression display increased expression of EGF receptors (EGFR), ABCG1, ABCG2 drug transporters, and MCT4 monocarboxylate transporters. In ovarian epithelium with chemo-resistant properties, elevated expression of CD147 and γ lewis antigen has been observed. The γ lewis antigen, as a part of the CD147 structure, could affect chemo-resistance in ovarian cancer by stimulating the ERK1/2 signaling pathway, making CD147 a potential clinical and prognostic marker.
 
Chemo-resistant colorectal cancer (CRC) samples exhibit higher levels of CypA, predicting poor prognosis. Cyclosporine A, targeting CypA, shows promising efficacy against chemo-resistant CRC when combined with chemotherapy. CyPA inhibitors, such as alisporivir, can inhibit the replication of SARS-CoVs and MERS, with ribavirin enhancing the antiviral activity of alisporivir.
 
Conclusion
The evidence presented highlights the crucial role of CD147 and CyPA in COVID-19 severity, cancer progression, and chemotherapy resistance for cancer patients with COVID-19. CD147 and CyPA are potential therapeutic targets for COVID-19, with the added benefit of hindering cancer progression and chemo-resistance in cancer patients with COVID-19.
 
The researchers hypothesize that HIF-1α activation during COVID-19 infection increases the expression of CD147 and CyPA, suggesting risk factors for long-term COVID-19 complications in cancer patients. This hypothesis encourages further investigation into the effects of hypoxic conditions and HIF-1α stimulation by SARS-CoV-2 infection on tumor cells. Ultimately, this study may provide insight into developing novel therapeutic approaches for cancer patients with COVID-19, reducing mortality rates and treatment failure.
 
The Iranian researchers' hypothesis and study findings were published as a correspondence in the peer reviewed journal: Infectious Agents and Cancer (BMC).
https://infectagentscancer.biomedcentral.com/articles/10.1186/s13027-023-00501-2
 
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