Today's Kaposi sarcoma is not the same as it was 40 years ago, or is it?

Damania, Blossom; Dittmer, Dirk P.

doi:10.1002/jmv.28773

Cited by 12 publications

(8 citation statements)

References 192 publications

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“…This is due to the high prevalence and early acquisition of KSHV and the unresolved HIV epidemic on the African continent (reviewed in ref. 41 ). Because in endemic regions, KSHV is acquired in early childhood, and because there are still instances of mother-to-child transmission for HIV, pediatric KS remains a common childhood cancer ( 13 ).…”

Section: Discussionmentioning

confidence: 99%

Pediatric HIV+ Kaposi sarcoma exhibits clinical, virological, and molecular features different from the adult disease

Caro-Vegas,

Peng,

Juarez

et al. 2023

JCI Insight

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BACKGROUND Kaposi sarcoma (KS) is among the most common childhood cancers in Eastern and Central Africa. Pediatric KS has a distinctive clinical presentation compared with adult KS, which includes a tendency for primary lymph node involvement, a considerable proportion of patients lacking cutaneous lesions, and a potential for fulminant disease. The molecular mechanisms or correlates for these disease features are unknown. METHODS This was a cross-sectional study. All cases were confirmed by IHC for KS-associated herpesvirus (KSHV) LANA protein. Baseline blood samples were profiled for HIV and KSHV genome copy numbers by qPCR and secreted cytokines by ELISA. Biopsies were characterized for viral and human transcription, and KSHV genomes were determined when possible. RESULTS Seventy participants with pediatric KS were enrolled between June 2013 and August 2019 in Malawi and compared with adult patients with KS. They exhibited high KSHV genome copy numbers and IL-6/IL-10 levels. Four biopsies (16%) had a viral transcription pattern consistent with lytic viral replication. CONCLUSION The unique features of pediatric KS may contribute to the specific clinical manifestations and may direct future treatment options. FUNDING US National Institutes of Health U54-CA-254569, PO1-CA019014, U54-CA254564, RO1-CA23958.

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Section: Discussionmentioning

confidence: 99%

Pediatric HIV+ Kaposi sarcoma exhibits clinical, virological, and molecular features different from the adult disease

Caro-Vegas,

Peng,

Juarez

et al. 2023

JCI Insight

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“…In sub-Saharan Africa, KS remains as the predominant cancer in both immunocompetent and immunocompromised individuals ( 1 ). Anti-cancer therapies are often ineffective against KS, and there is no vaccine or anti-KSHV therapy that can prevent or eliminate persistent KSHV infection ( 3 – 5 ). As a result, KS continues to be an urgent cancer, causing significant mortality and morbidity in the affected populations worldwide ( 3 , 6 ).…”

Section: Introductionmentioning

confidence: 99%

“…Numerous cofactors have been implicated in KSHV-associated malignancies. KSHV mostly causes cancers in patients with suppressed immunity, particularly in AIDS-related KS ( 2 , 5 ). HIV products such as Tat, Vpr, and Nef proteins also regulate KSHV replication and promote the proliferation of KS tumor cells ( 8 – 12 ).…”

Section: Introductionmentioning

confidence: 99%

Activation of glucocorticoid receptor signaling inhibits KSHV-induced inflammation and tumorigenesis

Chen,

Ding,

Wang

et al. 2024

mBio

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Hyperinflammation is the hallmark of Kaposi’s sarcoma (KS), the most common cancer in AIDS patients caused by Kaposi’s sarcoma-associated herpesvirus (KSHV) infection. However, the role and mechanism of induction of inflammation in KS remain unclear. In a screening for inhibitors of KSHV-induced oncogenesis, over half of the identified candidates were anti-inflammatory agents including dexamethasone, which functions by activating glucocorticoid receptor (GR) signaling. Here, we examined the mechanism mediating KSHV-induced inflammation. We found that numerous inflammatory pathways were activated in KSHV-transformed cells. Particularly, interleukin-1 alpha (IL-1α) and IL-1 receptor antagonist (IL-1Ra) from the IL-1 family were the most induced and suppressed cytokines, respectively. We found that KSHV miRNAs mediated IL-1α induction while both miRNAs and vFLIP mediated IL-1Ra suppression. Furthermore, GR signaling was inhibited in KSHV-transformed cells, which was mediated by vFLIP and vCyclin. Dexamethasone treatment activated GR signaling and inhibited cell proliferation and colony formation in soft agar of KSHV-transformed cells but had a minimal effect on matched primary cells. Consequently, dexamethasone suppressed the initiation and growth of KSHV-induced tumors in mice. Mechanistically, dexamethasone suppressed IL-1α but induced IL-1Ra expression. Treatment with recombinant IL-1α protein rescued the inhibitory effect of dexamethasone while overexpression of IL-1Ra caused a weak growth inhibition of KSHV-transformed cells. Furthermore, dexamethasone induced IκBα expression resulting in inhibition of the NF-κB pathway and IL-1α expression. These results reveal an important role of the IL-1 pathway in KSHV-induced inflammation and oncogenesis, which can be inhibited by dexamethasone-activated GR signaling, and identify IL-1-mediated inflammation as a potential therapeutic target for KSHV-induced malignancies. IMPORTANCE Kaposi’s sarcoma (KS) is the most common cancer in HIV-infected patients caused by Kaposi’s sarcoma-associated herpesvirus (KSHV) infection. Hyperinflammation is the hallmark of KS. In this study, we have shown that KSHV mediates hyperinflammation by inducing IL-1α and suppressing IL-1Ra. Mechanistically, KSHV miRNAs and vFLIP induce hyperinflammation by activating the NF-κB pathway. A common anti-inflammatory agent dexamethasone blocks KSHV-induced hyperinflammation and tumorigenesis by activating glucocorticoid receptor signaling to suppress IL-1α and induce IL-1Ra. This work has identified IL-1-mediated inflammation as a potential therapeutic target and dexamethasone as a potential therapeutic agent for KSHV-induced malignancies.

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“…Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically associated with Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), multicentric Castleman's disease (MCD) and KSHV inflammatory cytokine syndrome (KICS) (Damania and Dittmer, 2023;He et al, 2019). The life cycle of KSHV has two phases including latency and lytic replication.…”

Section: Introductionmentioning

confidence: 99%

METTL16 Controls Kaposi’s Sarcoma-Associated Herpesvirus Replication by RegulatingS-Adenosylmethionine Cycle

Zhang

Meng

Feng

et al. 2023

Preprint

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Oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV) consists of latent and lytic replication phases, both of which are important for the development of KSHV-related cancers. As one of the most abundant RNA modifications, N6-methyladenosine (m6A) and its related complexes regulate KSHV life cycle. However, the role of METTL16, a new RNA methyltransferase, in KSHV life cycle remains unknown. In this study, we have identified a suppressive role of METTL16 in KSHV lytic replication. METTL16 knockdown increased while METTL16 overexpression reduced KSHV lytic replication. METTL16 binding to and writing of m6A on MAT2A transcript are essential for its splicing, maturation and expression. As a rate-limiting enzyme in the methionine-S-adenosylmethionine (SAM) cycle, MAT2A catalyzes the conversion of L-methionine to SAM required for the transmethylation of protein, DNA and RNA, transamination of polyamines, and transsulfuration of cystathionine. Consequently, knockdown or chemical inhibition of MAT2A reduced intracellular SAM level and enhanced KSHV lytic replication. In contrast, SAM treatment was sufficient to inhibit KSHV lytic replication and reverse the effect of the enhanced KSHV lytic program caused by METTL16 or MAT2A knockdown. Mechanistically, METTL16 or MAT2A knockdown increased while SAM treatment decreased the intracellular reactive oxygen species level by altering glutathione level, which is essential for efficient KSHV lytic replication. These findings demonstrate that METTL16 suppresses KSHV lytic replication by modulating the SAM cycle to maintain intracellular SAM level and redox homeostasis, thus illustrating the linkage of KSHV life cycle with specific m6A modifications, and cellular metabolic and oxidative conditions.

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Today's Kaposi sarcoma is not the same as it was 40 years ago, or is it?

Cited by 12 publications

References 192 publications

Pediatric HIV+ Kaposi sarcoma exhibits clinical, virological, and molecular features different from the adult disease

Pediatric HIV+ Kaposi sarcoma exhibits clinical, virological, and molecular features different from the adult disease

Activation of glucocorticoid receptor signaling inhibits KSHV-induced inflammation and tumorigenesis

METTL16 Controls Kaposi’s Sarcoma-Associated Herpesvirus Replication by RegulatingS-Adenosylmethionine Cycle

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