基于调控PPAR/Prox-1轴抑制淋巴内皮转化的千层纸素A抑制KSHV vIL-6致瘤的机制研究

Kaposi's sarcoma (KS), the most frequent malignant neoplasia found in AIDS or organ transplant recipients, is caused by kaposi's sarcoma associated herpes virus (KSHV), which also known as herpes virus-8 (HHV-8). KSHV encodes a human interleukin-6 mimic, which was named as vIL-6, should be specially reponsiable for the KS onset. Accordingly, by modulating JAK/STAT/AKT/Prox-1 axis, vIL-6 transforms vascular endothelial cells to lymphatic ones, and potently induces angiogenesis and tumorigenesis. Despite the poor prognosis, however, no drug for the disease is available. Oroxylin A is a national Class I anti-tumor drugs, with evidence that it has a significant anti-angiogenic and anti-tumorigenic capacity. Our preliminary results showed oroxylin A can inhibit cell proliferation and colony formation induced by vIL-6 in vitro. Notably, oroxylin A blocked the vascular to lymphatic endothelial cells transformation. In this study, we will further investigate the effect and the underlying mechanisms of Oroxylin A on lymphatic reprogramming and angioma formation of vIL-6 in vitro and in vivo. With the consummation of research for Oroxylin A, our study will aid in finding the candidates for KS treatment, while the learning from lymphatic reprogramming will highlight the mechanism of tumorigenesis.

卡波氏肉瘤病毒（KSHV）编码产物病毒白细胞介素-6（vIL-6）通过调控JAK/STAT/AKT/Prox-1信号轴诱导血管/淋巴内皮细胞转化，最终导致KS肿瘤发生。尽管KS是艾滋病和器官移植患者的最常见肿瘤，但至今仍无特效药物。千层纸素A（Oroxylin A）是国家抗肿瘤I类新药，具有显著抗血管和抗肿瘤作用。本研究在体外证实千层纸素A抑制vIL-6诱导细胞增殖、克隆形成、微管形成，以及抑制淋巴内皮细胞转化的基础上，进一步通过体内实验验证千层纸素A对vIL-6诱导淋巴内皮细胞转化的影响，并着重探讨PPAR家族在千层纸素A抑制vIL-6诱导淋巴内皮细胞转化中的作用。本研究围绕淋巴内皮细胞转化这一中心，研究千层纸素A通过双向调控PPAR家族，抑制JAK/STAT/AKT/Prox-1信号轴，从而实现抗KS作用。本研究首次探讨了中药分子在淋巴内皮细胞转化中的作用，对肿瘤转移防治具有重要意义。

卡波氏肉瘤病毒（KSHV）编码产物病毒白细胞介素-6（vIL-6）通过调控JAK/STAT/AKT/Prox-1信号轴诱导血管/淋巴内皮细胞转化，最终导致KS肿瘤发生。尽管KS是艾滋病和器官移植患者的最常见肿瘤，但至今仍无特效药物。千层纸素A（Oroxylin A）是国家抗肿瘤I类新药，具有显著抗血管和抗肿瘤作用。本研究通过体内外试验证实千层纸素A抑制vIL-6诱导内皮细胞增殖、迁移和血管形成。本研究围绕血管/淋巴内皮细胞转化这一中心，阐明千层纸素A通过激活PPARγ，抑制PROX1/VEGFR3信号轴，从而实现抗KS作用。不仅如此，本研究首次发现了血管/淋巴内皮细胞转化在乳腺癌转移中的重要意义，为肿瘤转移防治提供了新思路和新依据。