H19/IGF-1R正反馈环在前列腺癌增殖凋亡中的作用及芒柄花黄素对其的干预作用

前列腺癌属于常见的几种恶性肿瘤之一，也是发病率最高的男性肿瘤。研究表明H19、IGF-1R在前列腺癌发生、发展都扮演着重要角色，但H19/IGF-1R正反馈环对前列腺癌作用未见报道。课题组2012-2014年研究表明芒柄花黄素在体外抑制前列腺癌细胞PC-3增殖，诱导其凋亡，这可能是通过下调ERK1/2、Akt及IGF-1R蛋白磷酸化水平实现。预实验显示芒柄花黄素能够下调lncRNA H19表达，同时外源性H19可增加IGF-1R的表达。据此，我们推测芒柄花黄素可能通过干预H19/IGF-1R正反馈环，影响下游信号通路（MAPK/PI3K）发挥抗前列腺癌作用。本项目拟通过细胞生物学、分子生物学、双荧光素酶等技术，观察H19/IGF-1R正反馈环、信号转导通路及凋亡相关因子的交互式对话，重点论证芒柄花黄素对H19/IGF-1R正反馈环的作用，为同类药物防治前列腺癌提供新靶点、新思路。

Prostate cancer is the first most common cancer among men in western countries. And as the second leading cause of cancer-related deaths in men, prostate cancer is the cause of 10 % of all male cancer deaths. Standard treatments for prostate cancer include chemotherapy and operation could improve the outcome of prostate cancer patients, which deliberately cause fatal toxicity. Previous studies have demonstrated that H19 and IGF-1R played improtant roles in prostate cancer. The isoflavone formononetin is a phytoestrogen and one of the main active components of red clover plants. A previous study by our group have shown that formononetin also significantly suppressed prostate cancer cell proliferation via the extracellular signal regulated kinase1/2 (ERK1/2) mitogen-activated protein kinase (MAPK), Akt and the insulin-like growth factor 1 receptor (IGF-1R) pathway Furthermore, our previous studies confirmed that formononetin downregulated the level of H19 and H19 upregulated the level IGF-1R. Based on the above information, we hypothesize that the positive feedback loop of H19/IGF-1R may also be involved in the antiproliferative effect induced by formononetin in prostate cancer cells. By using MTT assay, TUNEL, Hoechst, flow cytometry, Western blot, qPCR, Xenograft tumor growth, immunohistochemistry, and so on, we will identify an upregulated or downregulated the positive feedback loop of H19/IGF-1R in prostate cancer cells that was able to interfere with MAPK/PI3K signaling pathways in vitro and in vivo. Furthermore, we focus on the relationship among formononet, MAPK/PI3K signaling pathways and the positive feedback loop of H19/IGF-1R, which may provide experimental foundation for formononet 's future clinical use for prostate cancer.