RNA-Seq of Kaposi's sarcoma reveals alterations in glucose and lipid metabolism.

For Yue Tso,Charles Wood,Owen Ngalamika,Eun Hee Kwon,Salum J Lidenge,Paul M Lieberman,John T West,Jayamanna Wickramasinghe,Andrew V Kossenkov,John R Ngowi,Julius Mwaiselage

doi:10.1371/journal.ppat.1006844

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi’s sarcoma (KS). It is endemic in a number of sub-Saharan African countries with infection rate of >50%. The high prevalence of HIV-1 coupled with late presentation of advanced cancer staging make KS the leading cancer in the region with poor prognosis and high mortality. Disease markers and cellular functions associated with KS tumorigenesis remain ill-defined. Several studies have attempted to investigate changes of the gene profile with in vitro infection of monoculture models, which are not likely to reflect the cellular complexity of the in vivo lesion environment. Our approach is to characterize and compare the gene expression profile in KS lesions versus non-cancer tissues from the same individual. Such comparisons could identify pathways critical for KS formation and maintenance. This is the first study that utilized high throughput RNA-seq to characterize the viral and cellular transcriptome in tumor and non-cancer biopsies of African epidemic KS patients. These patients were treated anti-retroviral therapy with undetectable HIV-1 plasma viral load. We found remarkable variability in the viral transcriptome among these patients, with viral latency and immune modulation genes most abundantly expressed. The presence of KSHV also significantly affected the cellular transcriptome profile. Specifically, genes involved in lipid and glucose metabolism disorder pathways were substantially affected. Moreover, infiltration of immune cells into the tumor did not prevent KS formation, suggesting some functional deficits of these cells. Lastly, we found only minimal overlaps between our in vivo cellular transcriptome dataset with those from in vitro studies, reflecting the limitation of in vitro models in representing tumor lesions. These findings could lead to the identification of diagnostic and therapeutic markers for KS, and will provide bases for further mechanistic studies on the functions of both viral and cellular genes that are involved.

Highlights

Kaposi’s sarcoma (KS) is a multi-focal pleomorphic, highly vascularized tumor that is one of the AIDS defining illnesses
We found that viral genes involved in latency and immune modulation are most commonly expressed among KS patients
Cellular genes involved in lipid and glucose metabolism disorder pathways are significantly affected by the presence of Kaposi’s sarcoma-associated herpesvirus (KSHV)

Summary

Introduction

Kaposi’s sarcoma (KS) is a multi-focal pleomorphic, highly vascularized tumor that is one of the AIDS defining illnesses. There are four types of KS: iatrogenic, classic, endemic and epidemic/AIDS-related KS [1,2,3,4]. Endemic and epidemic KS are the most common forms in sub-Sahara Africa. Endemic KS occurs in HIV-1 negative African patients of both genders. The presentation in both genders at varying ages differentiates this form of KS from classical KS found mostly in elderly Mediterranean men. Epidemic KS occurs in patients who are HIV-1 positive, and along with iatrogenic KS, which results from chemical immunosuppression, highlights the role of immune dysregulation in KS development. The prognosis of KS patients in sub-Sahara Africa is generally poor, often due to delayed diagnosis and late initiation of treatment [7]. Even after receiving anti-retroviral drugs therapy (ART), the mortality of epidemic KS patient is often high due to advanced KS disease staging, simultaneous advanced HIV-1 diagnosis and both HIV-1 and KS-immune reconstitution inflammatory syndromes [8]

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