KSHV 持续性感染口腔间充质干细胞与相关肿瘤发生的机制研究

Kaposi’s sarcoma (KS) remains the most common malignancy in AIDS patients. In AIDS-KS patients, oral cavity is often the first site or the only site of KS. Oral KS appears to be more aggressive and malignant than those occur on other sites such as the skin. AIDS-KS lessons are characterized by proliferating KSHV-infected spindle cells and intensive angiogenesis and inflammation. The origin of the spindle cells remains elusive. Recently we found that KSHV can efficiently infect oral mesenchymal stem cells (MSCs) and the infection leads to morphological changes and cells becomes spindle-shaped similar to KS cells. Furthermore, infected MSCs exhibit enhanced ability of adipogenesis, osteogenesis and angiogenesis. These discoveries prompted us to propose a hypothesis that oral MSCs are the primary cells of KSHV infection and the infected MSCs can undergo mesenchymal-to-endothelial transition (MET) and therefore be transformed to KS malignant cells. In the proposed project, we will examine and prove this hypothesis by (1) characterizing oral MSCs infected by KSHV for their stem cell property, differentiation ability and tumor transformation potential; (2) elucidating the process and underlying mechanism of MET in infected oral MSCs. In addition, efforts will be made to identify small molecule compounds that inhibit KSHV infection of oral MSCs and block tumorigenesis of infected MSCs, exploring the potentials of the compounds to be used as new therapeutic strategies and new drugs to treat KS and other KSHV-associated malignancies.

卡波氏肉瘤(KS)是艾滋病群体中最主要的恶性肿瘤。艾滋病相关KS病人中，KS往往首先发生在口腔。口腔KS的恶性程度直接反应病人整体KS的进程。但是关于KSHV很多重要的问题还没有解决。 KSHV感染和藏匿在人体什么细胞里？怎样促进KS肿瘤的发生？KS肿瘤细胞从何而来? 我们最近发现人类口腔间充质干细胞（OMSC) 能被KSHV高效感染，并促进其分化，使之具备更强的成脂，成骨和成血管特性。这些发现引导我们提出了一系列新的KSHV致癌理论。1）OMSC可能是KSHV初始感染的目标。2）KSHV感染劫持OMSC细胞发生间充质-内皮细胞转化导致卡波氏肉瘤的产生。我们通过本项目1）研究KSHV感染OMSC，建立潜伏感染和促进分化的机制，希望找到KSHV潜伏感染的OMSC是KS纺梭状细胞前体的证据；2）阐明KSHV转化OMSC诱导其癌变的机制；3）寻求阻止KSHV感染和医治KS的新途径和新药物。

卡波西式肉瘤（KS）是由KSHV感染引发的具有极强血管增生和转移能力的肿瘤。由于肿瘤细胞表达多种不同类型细胞的特异性标志物，目前肿瘤细胞起源尚无定论。传统观点认为KS肿瘤细胞起源于内皮细胞，但KSHV感染的内皮细胞在体外不能永生化并在裸鼠体内不能形成肿瘤。为此，本研究结合KS临床相关现象，提出KS肿瘤细胞起源于口腔间充质干细胞（MSC）的假说。基于此假说的基础，本研究主要关注以下三个问题：① KS肿瘤细胞是否可能起源于口腔MSC；②KSHV诱导口腔MSC转化为KS肿瘤细胞涉及的相关机制；③ 筛选可以抑制KSHV病毒复制及肿瘤发生的新型药物。通过一系列实验发现：① KS肿瘤细胞确实起源于口腔MSC，KSHV感染的口腔MSC可以获得多种类似KS肿瘤细胞的表征；② KSHV通过诱导间充质-内皮转化（MEndT）促使口腔MSC转化为KS肿瘤细胞，这个过程主要依赖于细胞基因PROX1以及多种病毒癌基因的调控；③ APE1在KSHV诱导口腔MSC癌变过程中发挥主要作用，同时本研究筛选到APE1新型的小分子化合物C10，该化合物可能是治疗KS潜在的新型药物； ④ KSHV感染与骨肉瘤发生具有相关性。这些发现对于了解KSHV相关肿瘤的发生机制以及改善抗肿瘤治疗方法提供了新的方向。