LRIG1在前列腺癌中的生物学功能和分子调控机制的研究

中晚期前列腺癌（PCa）依然是高死亡率的重要原因，但其发病机制仍不十分清楚。研究发现LRIG1在维持皮肤、小肠等组织干细胞中起重要的调节作用，且在多种肿瘤组织中低表达，但LRIG1在PCa中的功能还不清楚。我们的前期工作发现，在PSA-/lo细胞（富集PCa干细胞）中LRIG1高表达，且与雄性激素受体（AR）表达呈正相关。本课题拟利用人类PCa临床样本和细胞株，探讨LRIG1在PCa中的表达与患者预后的关系，分析过表达和敲减LRIG1对细胞生物学行为和成瘤能力的影响，揭示其在PCa中的功能；此外，探讨其与雄性激素/AR通路的关系，并阐明是否通过负性调控ErbBs发挥其功能，为诊断和治疗PCa提供新思路。

Prostate Cancer (PCa) is one of the most malignant cancers affecting men worldwide. The etiology for PCa development is poorly understood. Recent studies have shown that LRIG1 (Leucine-rich repeats and immunoglobulin-like domains protein 1) plays vital roles in regulating normal stem cell homeostasis and quiescence in several tissues including small intestine and skin. LRIG1 is downregulated in several human cancers, and it has tumor suppressive functions via negatively regulating the mitogenic signaling from the ErbBs receptor tyrosine kinases. However, its role in regulating prostate cancer (PCa) development has not been well investigated. In our earlier studies, we found that LRIG1 level is highly expressed in the PSA-/lo prostate cancer stem cells and human PCa tissues. Nevertheless, LRIG1 can inhibit PCa cell proliferation in vitro. Further investigation has suggested LRIG1 level is positively correlated with androgen receptor (AR), and LRIG1 has potential to restrict the oncogenic functions of AR and ErbBs in PCa cells. Thus, based on our preliminary data, our central hypothesis is that LRIG1 functions as an AR-induced prostate tumor suppressor to antagonize ErbBs during early PCa development. To test this hypothesis, we aim to achieve the following goals: 1) To further investigate LRIG1 expression level in human PCa tissues and its association with clinical prognosis; 2) To systematically examine the functions of LRIG1 in prostate cancer cells; 3) To elucidate the signaling relationship between AR, LRIG1 and ErbBs in PCa cells. Completing the current project herein will greatly advance our understanding of how LRIG1 exerts its tumor-suppressive in PCa development and will lay a solid foundation for the development of novel LRIG1-based therapeutics.