FOXO1在KSHV诱导的细胞恶性转化过程中的作用及其机制研究

病毒感染可导致11%人类肿瘤的发生。卡波氏肉瘤病毒（KSHV）是人类致癌病毒之一，也是卡波氏肉瘤（KS）和其他几种癌症的病因，然而其致癌机制仍不清楚。前期我们发现KSHV恶性转化细胞的代谢通路被重塑，包括糖酵解、谷氨酰胺分解、尿素循环等经典代谢途径。细胞内活性氧物质（ROS）通常来源于细胞代谢，因此，KSHV恶性转化细胞代谢通路的失调，极有可能影响宿主细胞ROS的水平。而FOXOs蛋白作为典型的ROS感知器，也可能相应地受到调控，从而调节细胞的恶性转化。在此基础上，我们拟以致癌病毒恶性转化的细胞为模型进一步研究：1）ROS在KSHV诱导的恶性细胞转化和肿瘤发生过程中的作用；2）FOXOs蛋白在KSHV诱导的细胞转化和肿瘤发生中的作用； 3）KSHV介导FOXO和ROS调节的分子机制。这些研究成果将揭示KSHV致癌的新机制，并为KS及其他肿瘤的治疗提供新的靶标。

Viral infection accounts for up to 11% of human cancer worldwide. Kaposi's sarcoma-associated herpesvirus (KSHV) is one of oncogenic herpesvirus and is the etiologic agent of Kaposi’s Sarcoma (KS), and several other cancers. Despite intensive studies, the mechanism underlying KSHV-induced cellular transformation remains unclear. We have previously discovered that KSHV-transformed cells have rewired cellular metabolic pathways, such as glycolysis, glutaminolysis and urea cycle As a natural byproduct of normal aerobic metabolism, ROS is potentially dysregulated in KSHV-transformed cells due to the reprogrammed metabolic pathways. More importantly, FOXOs proteins are well characterized redox sensor and are hence speculated to be regulated in KSHV-transformed cells correspondingly. With these findings and by applying the oncogenic-transformed cell models, we will further investigate: 1) the role of ROS in KSHV-induced cellular transformation and tumorigenesis; 2) the role of FOXOs in KSHV-induced cellular transformation and tumorigenesis; 3) the mechanisms of KSHV-mediated regulation of FOXOs and ROS. These studies will reveal a novel mechanism for KSHV-induced tumorigenesis, and also provide new potential therapeutic targets for KS tumors and other cancers.