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

LRIG1 在前列腺癌和 CRPC 中的抑癌功能和分子调控

基本信息

批准号：
10360575
负责人：
Dean G Tang
金额：
$ 42.48万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10360575
关键词：
Adenocarcinoma Adult Androgen Antagonists Androgen Receptor Biochemical Biological Biological Process Cancer Patient Cancer Relapse Castration Cells Cysteine Cytoplasmic Tail Development Diagnostic Down-Regulation EGFR gene Epigenetic Process Excision Exhibits Feedback Foundations Gene Expression Profiling Genetic Genetic Transcription Goals Heterogeneity Immunoglobulin Domain Intestines Knowledge Leucine-Rich Repeat MYC Family Protein Malignant Neoplasms Malignant neoplasm of prostate Mediating Messenger RNA Metastatic Prostate Cancer Modeling Molecular Mus Mutation Neoplasm Metastasis Neuroendocrine Prostate Cancer Oncogene Activation Oncogenic PTEN gene Paper Pathway interactions Patients Pattern Peptide Signal Sequences Phenotype Play Population Prognostic Marker Property Prostate Prostatic Neoplasms Protein Tyrosine Kinase Proteins PubMed Publishing Receptor Protein-Tyrosine Kinases Regulation Reporting Resistance Role Series Signal Transduction Specimen Stem Cell Factor Structure TP53 gene Tertiary Protein Structure Testing Therapeutic Therapeutic Agents Therapeutic Effect Transgenic Model Transgenic Organisms Transmembrane Domain Tumor Suppression Tumor Suppressor Proteins Undifferentiated Work Xenograft Model Xenograft procedure adult stem cell androgen deprivation therapy androgen sensitive base castration resistant prostate cancer cohort enzalutamide mouse model neoplastic cell novel overexpression prostate cancer cell prostate cancer model prostate cancer progression response stem cell population stem cells stemness transcription factor transdifferentiation tumor tumorigenesis tumorigenic

项目摘要

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.

本项目旨在系统研究LRIG1的生物学功能和分子调控