Elevated iNOS and 3′-nitrotyrosine in Kaposi's Sarcoma tumors and mouse model

IF 4.7 Q1 VIROLOGY Tumour Virus Research Pub Date : 2023-06-01 DOI:10.1016/j.tvr.2023.200259
Olga Vladimirova , Samantha Soldan , Chenhe Su , Andrew Kossenkov , Owen Ngalamika , For Yue Tso , John T. West , Charles Wood , Paul M. Lieberman
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引用次数: 4

Abstract

Kaposi's Sarcoma (KS) is a heterogenous, multifocal vascular malignancy caused by the human herpesvirus 8 (HHV8), also known as Kaposi's Sarcoma-Associated Herpesvirus (KSHV). Here, we show that KS lesions express iNOS/NOS2 broadly throughout KS lesions, with enrichment in LANA positive spindle cells. The iNOS byproduct 3-nitrotyrosine is also enriched in LANA positive tumor cells and colocalizes with a fraction of LANA-nuclear bodies. We show that iNOS is highly expressed in the L1T3/mSLK tumor model of KS. iNOS expression correlated with KSHV lytic cycle gene expression, which was elevated in late-stage tumors (>4 weeks) but to a lesser degree in early stage (1 week) xenografts. Further, we show that L1T3/mSLK tumor growth is sensitive to an inhibitor of nitric oxide, L-NMMA. L-NMMA treatment reduced KSHV gene expression and perturbed cellular gene pathways relating to oxidative phosphorylation and mitochondrial dysfunction. These finding suggest that iNOS is expressed in KSHV infected endothelial-transformed tumor cells in KS, that iNOS expression depends on tumor microenvironment stress conditions, and that iNOS enzymatic activity contributes to KS tumor growth.

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卡波西肉瘤肿瘤及小鼠模型中iNOS和3′-硝基酪氨酸升高
卡波西肉瘤(KS)是一种由人类疱疹病毒8型(HHV8)引起的异质性多灶性血管恶性肿瘤,也称为卡波西氏肉瘤相关疱疹病毒(KSHV)。在这里,我们发现KS病变在整个KS病变中广泛表达iNOS/NOS2,在LANA阳性梭形细胞中富集。iNOS副产物3-硝基酪氨酸也在LANA阳性肿瘤细胞中富集,并与一部分LANA核体共定位。我们发现iNOS在KS的L1T3/mSLK肿瘤模型中高度表达。iNOS表达与KSHV裂解周期基因表达相关,后者在晚期肿瘤(>4周)中升高,但在早期(1周)异种移植物中升高程度较低。此外,我们发现L1T3/mSLK肿瘤生长对一氧化氮抑制剂L-NMMA敏感。L-NMMA治疗降低了KSHV基因表达,并干扰了与氧化磷酸化和线粒体功能障碍有关的细胞基因通路。这些发现表明,iNOS在KS中KSHV感染的内皮转化的肿瘤细胞中表达,iNOS的表达取决于肿瘤微环境应激条件,并且iNOS酶活性有助于KS肿瘤生长。
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来源期刊
Tumour Virus Research
Tumour Virus Research Medicine-Infectious Diseases
CiteScore
6.50
自引率
2.30%
发文量
16
审稿时长
56 days
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