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Olfactomedin 4 Suppresses Prostate Cancer Cell Growth and Metastasis via Negativ

Olfactomedin 4 通过 Negativ 抑制前列腺癌细胞的生长和转移

基本信息

批准号：
8939810
负责人：
GRIFFIN RODGERS
金额：
$ 32.92万
依托单位：
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8939810
关键词：
13q12-13 13q14 13q14.3 14q American BRCA2 gene Biological Biological Process CXCL12 gene Cadherins Cancer Cell Growth Cancer Etiology Cathepsins Cell Adhesion Cell Proliferation Cell surface Cells Cessation of life Chromosomes Colon Carcinoma Colonic Neoplasms Diagnosis Diagnostic Ectopic Expression Evaluation Exons Family Family member Gene Expression Gene Expression Profile Gene Proteins Gene Targeting Genes Genetic Glycoproteins Goals Human Human Genome In Vitro Inflammation Knockout Mice Lectin Loss of Heterozygosity Malignant neoplasm of prostate Messenger RNA Metastatic Neoplasm to the Bone Molecular Mus Natural Immunity Neoplasm Metastasis Play Prostate Prostate Adenocarcinoma Prostatic Intraepithelial Neoplasias Prostatic Neoplasms RB1 gene Reporting Retinoblastoma Role Sampling Seminal fluid Serum Signaling Pathway Gene Solid Neoplasm Sonic hedgehog protein Stem cells Stomach Neoplasms Susceptibility Gene Tissues Tumor Suppressor Genes Tumor Suppressor Proteins age related cancer type cell growth epithelial to mesenchymal transition forkhead protein gene function human GW112 protein improved in vivo malignant breast neoplasm malignant stomach neoplasm men mouse model novel marker olfactomedin outcome forecast prognostic prostate cancer cell smoothened signaling pathway stem therapeutic target tumor progression

项目摘要

The human olfactomedin 4 gene (OLFM4) encodes an olfactomedin-related glycoprotein. OLFM4 is normally expressed in a limited number of tissues, including the prostate, but its biological functions in prostate are largely unknown. Loss of olfactomedin 4 (OLFM4) gene expression is associated with high grade of human prostate cancer. Genetics studies have found that deletions within the olfactomedin 4 (OLFM4) gene occur in approximately 25% of human prostate-cancer samples. To explore cellular and molecular mechanisms underlying OLFM4 functions, we investigated Olfm4-knockout mouse model and human prostate cancer cells that lack OLFM4 expression. Phenotypically studies of prostate from Olfm4-knockout mice found that sporadically developed prostatic intraepithelial neoplasia and prostatic adenocarcinoma in an age-dependent manner. The gene-expression signature of prostate tissues from Olfm4-knockout mice at 3 month-old and 15 month-old revealed significant changes for genes associated with prostate neoplastic progression. Sonic hedgehog-signaling pathway and target genes were significantly up-regulated in prostate from Olfm4-knockout mice. Importantly, we found Olfactomedin 4 inhibits prostate stem/progenitor cell growth and epithelial-to-mesenchymal transition (EMT) through down-regulated the hedgehog-signaling pathway genes and target genes activities. Moreover, we demonstrated that OLFM4 inhibited the hedgehog-signaling pathway via direct interaction with sonic hedgehog protein. These findings suggest that OLFM4 plays a critical role in prostate neoplastic progression and that OLFM4 protein has potential as a new marker for improving diagnostic/prognostic accuracy and likely targets for therapeutic approaches to prostate cancer.

人嗅觉调节蛋白4基因（OLFM 4）编码一种嗅觉调节蛋白相关糖蛋白。OLFM 4通常在包括前列腺在内的有限数量的组织中表达，但其在前列腺中的生物学功能在很大程度上是未知的。嗅觉调节蛋白4（OLFM 4）基因表达的缺失与高级别的人前列腺癌相关。遗传学研究发现，在大约25%的人类前列腺癌样本中发生了嗅觉调节蛋白4（OLFM 4）基因的缺失。为了探索OLFM 4功能的细胞和分子机制，我们研究了OLFM 4敲除小鼠模型和缺乏OLFM 4表达的人前列腺癌细胞。对Olfm 4基因敲除小鼠前列腺的表型研究发现，以年龄依赖性方式零星发生前列腺上皮内瘤变和前列腺腺癌。来自3个月大和15个月大的Olfm 4敲除小鼠的前列腺组织的基因表达特征揭示了与前列腺肿瘤进展相关的基因的显著变化。Olfm 4基因敲除小鼠前列腺中的Sonic hedgehog信号通路和靶基因表达显著上调。重要的是，我们发现Olfactomedin 4通过下调hedgehog信号通路基因和靶基因活性来抑制前列腺干/祖细胞生长和上皮-间质转化（EMT）。此外，我们证明了OLFM 4通过与音刺猬蛋白直接相互作用来抑制刺猬信号通路。这些发现表明，OLFM 4在前列腺肿瘤进展中起着关键作用，OLFM 4蛋白有潜力作为一种新的标志物，用于提高诊断/预后的准确性和可能的目标，前列腺癌的治疗方法。