Tumor-Suppressive Functions and Molecular Regulation of LRIG1 in Prostate Cancer and CRPC

本项目旨在系统研究LRIG1的生物学功能和分子调控 在前列腺癌(PCa)的发展和去势抵抗的PCa(CRPC)中。为什么这很重要，而且 重要吗？LRIG1(富含亮氨酸重复序列和免疫球蛋白样域蛋白1)是一种常见的 下调/缺失，在许多癌症中作为肿瘤抑制因子发挥作用。此外，LRIG1还发挥了关键作用 在调节成体(表皮和肠道)干细胞静止方面的作用。在这两个设置中，LRIG1强制 SC通过促进有丝分裂原降解和拮抗有丝分裂原抑制肿瘤发展 ERBB和相关蛋白酪氨酸激酶的信号转导。尽管这些批判性的知识 LRIG1、LRIG1、LRIG1、 我们的初步研究揭示了一个令人惊讶的发现：与许多公司下调或失去监管相反 在数百例被检测的前列腺癌标本中，肿瘤、LRIG1的mRNA和蛋白显著过表达。 引人注目的是，LRIG1水平的升高与患者更好的生存相关，这意味着一种肿瘤抑制作用 LRIG1在前列腺癌中的作用事实上，在多种模型中进行的广泛的异种移植研究提供了强有力的证据。 支持LRIG1的PCA抑制功能。通过开发新型前列腺特异性LRIG1转基因 模型中，我们进一步提供了LRIG1过表达抑制肿瘤发生的初步遗传学证据 在Hi-Myc和TraMP型号中都是如此。其他重要和新颖的初步发现表明：1)LRIG1 下调PCa细胞的内源性Myc；2)在治疗-幼稚的PCa细胞中，AR直接和主要 调节LRIG1基因转录；3)在CRPC中，LRIG1的表达变得异质性，表达减少，但 4)在CRPC中，AR和‘茎’因子可能在调节LRIG1的表达中起重要作用； 5)LRIG1对已建立的AR和AR-PCA模型具有“治疗”作用。 基于我们的初步观察，我们在这里测试LRIG1起作用的总体假设 作为PCA和CRPC中AR和干性调节的反馈肿瘤抑制因子，有三个特定的目标： 1)研究LRIG1在遗传性小鼠模型中的PCA抑制功能及其机制； 2)阐明AR调控的LRIG1在雄激素敏感性前列腺癌中的表达和功能的分子细节； 3)确定LRIG1在CRPC中的功能和调控。 我们将通过结合遗传小鼠和异种移植模型的肿瘤研究来实现这些目标 以机制为导向的细胞生物学、分子和生化方法。 意义：这个项目填补了我们对LRIG1在前列腺癌中的功能和调控知识的一个关键空白。 LRIG1令人印象深刻的肿瘤抑制功能及其与患者良好生存的相关性表明 LRIG1表达作为预后生物标志物的潜在应用。最后，我们的初步治疗结果 支持开发基于LRIG1的新型抗PCa和抗CRPC治疗药物的潜在用途。

This project aims to systematically investigate the biological functions and molecular regulation of LRIG1 in prostate cancer (PCa) development and in castration-resistant PCa (CRPC). Why is this important and significant? LRIG1 (leucine-rich repeats and immunoglobulin-like domains protein 1) is frequently downregulated/lost and functions as a tumor suppressor in many cancers. Furthermore, LRIG1 plays a critical role in regulating the quiescence of adult (epidermal and intestinal) stem cells. In both settings, LRIG1 enforces SC quiescence and inhibits tumor development via promoting degradation of and antagonizing mitogenic signaling from the ERBB and related protein tyrosine kinases. Despite this critical body of knowledge on LRIG1, little is known and few papers have been published about LRIG1 functions and regulation in PCa. Our preliminary studies revealed a surprising finding: in contrast to its downregulation or loss in many cancers, LRIG1 mRNA and protein are significantly overexpressed in hundreds of PCa specimen examined. Strikingly, increased LRIG1 levels correlate with better patient survival, implicating a tumor-suppressive function of LRIG1 in PCa. Indeed, extensive xenograft-based studies in multiple models provided strong support to PCa-suppressive functions of LRIG1. By developing a novel prostate-specific LRIG1 transgenic model, we further provide preliminary genetic evidence that LRIG1 overexpression suppresses tumorigenesis in both Hi-Myc and TRAMP models. Other important and novel preliminary findings demonstrate that: 1) LRIG1 downregulates endogenous Myc in PCa cells; 2) in treatment-naïve PCa cells, AR directly and predominantly regulates LRIG1 gene transcription; 3) in CRPC, LRIG1 expression becomes heterogeneous, is reduced, but persists; 4) in CRPC, both AR and `stemness' factors may play important roles in regulating LRIG1 expression; and 5) LRIG1 exhibits `therapeutic' effects on established AR+ and AR- PCa models. Based on our preliminary observations, here we test our overarching hypothesis that LRIG1 functions as an AR- and stemness-regulated feedback tumor suppressor in PCa and CRPC, with three Specific Aims: 1) Investigate PCa-suppressive functions of LRIG1 and underlying mechanisms in genetic mouse models; 2) Elucidate molecular details of AR-regulated LRIG1 expression and functions in androgen-sensitive PCa; 3) Determine functions and regulation of LRIG1 in CRPC. We shall accomplish these aims by combining tumor studies in genetic mouse and xenograft models with mechanism-oriented cell biological, molecular, and biochemical approaches. Significance: This project fills a critical gap in our knowledge on the functions and regulation of LRIG1 in PCa. The impressive tumor suppressive functions of LRIG1 and its association with good patient survival suggest the potential use of LRIG1 expression as a prognostic biomarker. Finally, our preliminary therapeutic results support potential utility of developing novel LRIG1-based anti-PCa and anti-CRPC therapeutics.