Abstract
Patients with diabetes are generally prone to pathogen infection and tumor progression. Here, we investigated the potential association between diabetes and Kaposi's sarcoma (KS), a tumor linked to infection with Kaposi's sarcoma-associated herpesvirus (KSHV). By using Taiwan's National Health Insurance Research Database, we found that diabetes is statistically associated with increased risk of KS in a case-control study. Since a high level of blood sugar is the hallmark of diabetes, we determined whether high glucose promotes both KSHV reactivation and infection, which are crucial for KS pathogenesis. Our results showed that high glucose significantly increases lytic reactivation of KSHV but not Epstein-Barr virus, another related human oncogenic gammaherpesvirus, in latently infected cells. Activation of the transcription factor AP1 by high glucose is critically required for the onset of KSHV lytic reactivation. We also demonstrated that high glucose enhances susceptibility of various target cells to KSHV infection. Particularly, in endothelial and epithelial cells, levels of specific cellular receptors for KSHV entry, including integrin α3β1 and xCT/CD98, are elevated under high glucose conditions, which correlate with the enhanced cell susceptibility to infection. Taken together, our studies implicate that the high-glucose microenvironment may be an important predisposing factor for KS development.
Highlights
Kaposi’s sarcoma (KS) is an endothelial cell-derived vascular tumor, which has four clinical forms including classic, African endemic, AIDS-related, and transplantrelated KS [1]
Since a high level of blood sugar is the hallmark of diabetes, we determined whether high glucose promotes both Kaposi’s sarcoma-associated herpesvirus (KSHV) reactivation and infection, which are crucial for KS pathogenesis
Logistic regression analysis revealed that the adjusted odds ratio (OR) of diabetes in KS patients was 2.26 (Table 1), indicating that there is a significant relationship between diabetes and the risk of KS
Summary
Kaposi’s sarcoma (KS) is an endothelial cell-derived vascular tumor, which has four clinical forms including classic, African endemic, AIDS-related, and transplantrelated KS [1]. All KS subtypes are linked to infection of Kaposi’s sarcoma-associated herpesvirus (KSHV), or known as human herpesvirus 8 (HHV-8) [2]. Latent infection with KSHV plays an essential role in viral persistence and tumorigenesis, numerous studies have shown that active lytic program of KSHV is crucial for KS pathogenesis and strongly correlates with KS progression and severity [2,3,4,5]. Accumulating evidence reveals that patients with diabetes are more susceptible to pathogen infection and are more likely to develop certain cancers [10, 11], the causal association between diabetes and KS still needs to be further demonstrated
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