Diabetes and risk of Kaposi’s sarcoma: effects of high glucose on reactivation and infection of Kaposi’s sarcoma-associated herpesvirus
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Pey-Jium Chang1,2,3, Yao-Hsu Yang4,5,6,7, Pau-Chung Chen6,8, Lee-Wen Chen9,10, Shie-Shan Wang10, Ying-Ju Shih1, Li-Yu Chen1, Chi-Jen Chen5, Chien-Hui Hung1 and Chun-Liang Lin2,3
1Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang-Gung University, Taoyuan, Taiwan
2Department of Nephrology, Chang-Gung Memorial Hospital, Chiayi, Taiwan
3Kidney and Diabetic Complications Research Team (KDCRT), Chang-Gung Memorial Hospital, Chiayi, Taiwan
4Department of Traditional Chinese Medicine, Chang-Gung Memorial Hospital, Chiayi, Taiwan
5Center of Excellence for Chang Gung Research Datalink, Chang-Gung Memorial Hospital, Chiayi, Taiwan
6Institute of Occupational Medicine and Industrial Hygiene, National Taiwan University College of Public Health, Taipei, Taiwan
7School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
8Department of Environmental and Occupational Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
9Department of Respiratory Care, Chang-Gung University of Science and Technology, Chiayi, Taiwan
10Department of Pediatric Surgery, Chang-Gung Memorial Hospital, Chiayi, Taiwan
Pey-Jium Chang, email: [email protected]
Chun-Liang Lin, email: [email protected]
Keywords: Kaposi’s sarcoma, diabetes, KSHV, high glucose, lytic replication
Received: February 13, 2017 Accepted: June 18, 2017 Published: July 28, 2017
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.
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