局部IGF1调节ABHD2表达影响前列腺癌进展的分子机制

胰岛素样生长因子（IGF1）是生长激素（GH）下游的信号因子，在多个器官的生长发育中发挥着重要作用，近年研究表明IGF1有促进细胞有丝分裂和细胞分化的功能，促进恶性肿瘤的发生和转移。因此，阐明IGF1对肿瘤发展的调控机制有着非常重大的意义。前期结果显示，内分泌的IGF1可通过调节FOXO3A/BIM促进前列腺癌进展，而对于自分泌和旁分泌的IGF1，其作用效果与机制尚不明确，在此基础上，本课题拟利用前期构建的模式动物小鼠，探讨以下科学问题：（1）前列腺局部敲除IGF1对小鼠发生前列腺癌恶性表型的影响；（2）利用分子生物学实验手段及高通量基因组测序等技术，深入挖掘由IGF1介导的代谢通路对恶性肿瘤的作用机制；（3）在细胞系水平研究IGF1通过改变代谢通路影响前列腺进展的信号通路，并在临床样本中予以验证。本研究将为深入理解IGF1的生物学功能提供依据，同时有助于提供前列腺癌精准防治潜在靶点。

Insulin-like growth factor (IGF1) is a key downstream mediator of the growth hormone (GH) signaling pathway, which regulates cellular homeostasis and plays significant roles in the growth and development of multiple organs. Recently, the role of IGF1 in cell mitosis and tumor progression in many cancers has been appreciated but is not well characterized in prostate cancer (PC). Our previous study identified circulating IGF1 promotes PC by regulating FOXO3A/BIM signal pathways in the mouse model. However, the role of autocrine and paracrine IGF1 (local IGF1) and related mechanisms are still unknown. By using the mouse models we already have, this project is designed in the following aspects: (1) Phenotypes of PC progression in prostate-specific IGF1 knockout mice; (2) By using modern molecular methods, for example, high-throughput sequencing, we’ll explore the mechanism of local IGF1-mediated metabolic pathways in PC; (3) Using human PC cell lines and specimens to probe how local IGF1 regulate PI3K/AKT pathway, and whether this function affects metabolic signaling and ABHD2 expression. These studies have the most important signification for enriching the understanding of IGF1 biological functions and developing personalized genome-based clinical therapies.