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

• 批准号: 10012676
• 负责人: GRIFFIN RODGERS
• 金额: $ 52.01万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 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/10012676
• 关键词: 13q12; 14q; Advanced Malignant Neoplasm; American; Bioinformatics; Biological; Biological Markers; Biological Process; CXCL12 gene; Cadherins; Cancer Cell Growth; Cancer Etiology; Cancerous; Cathepsins; Cell Adhesion; Cell Proliferation; Cell surface; Cells; Cessation of life; Chromosomes; Clinical; Colon Carcinoma; Colonic Neoplasms; DU145; Data Set; Diagnosis; Ectopic Expression; Epithelial; Evaluation; Exhibits; Exons; FOXO1A gene; Family; Family member; Gene Expression; Genes; Gleason Grade for Prostate Cancer; Goals; Human; Human Genome; In Vitro; Inflammation; Lectin; Loss of Heterozygosity; Malignant Neoplasms; Malignant neoplasm of prostate; Mesenchymal; Messenger RNA; Metastatic Neoplasm to the Bone; Methylation; Molecular; Mus; Natural Immunity; Negativism; Neoplasm Metastasis; Normal Cell; Normal tissue morphology; OLFM4 gene; PC3 cell line; Patients; Play; Promoter Regions; Prostate; Prostate Adenocarcinoma; Prostate-Specific Antigen; Prostatic Neoplasms; Proteins; Recurrence; Reporting; Retinoblastoma; Role; Seminal fluid; Serum; Site; Solid Neoplasm; Stomach Neoplasms; Susceptibility Gene; Tissues; Tumor Suppressor Genes; Tumor Suppressor Proteins; cancer type; candidate marker; cell growth; forkhead protein; improved; in vivo; in vivo Model; knock-down; mRNA Expression; malignant breast neoplasm; malignant stomach neoplasm; men; neoplastic cell; novel; olfactomedin; outcome forecast; programs; prostate cancer cell; prostate cancer progression; protein expression; restoration; tumor growth; tumor initiation

The olfactomedin 4 (OLFM4) gene has been analyzed as a tumor-suppressor gene and a putative biomarker in many cancers. In our study, we analyzed the relationship of OLFM4 expression with clinicopathological features and with CpG site methylation in the OLFM4 gene promoter region in human primary prostate adenocarcinoma. OLFM4 protein expression was significantly reduced in prostate cancer tissue compared to adjacent normal tissue and was further significantly reduced in more advanced cancers. Bioinformatic studies with clinical datasets revealed that primary prostate adenocarcinoma patients with reduced OLFM4 mRNA expression exhibited higher Gleason scores and higher preoperative serum prostate-specific antigen levels, as well as lower recurrence-free survival. Three of the eight CpG sites in the OLFM4 gene promoter region were hypermethylated in cancerous prostate cells compared to adjacent normal cells, and reduced methylation of eight CpG sites was associated with increased OLFM4 mRNA expression in RWPE1 and PC-3 cells. Furthermore, knockdown of OLFM4 gene expression was associated with enhanced epithelial-mesenchymal transition (EMT)-marker expression in RWPE immortalized normal prostate cells. In contrast, restoration of OLFM4 expression in PC-3 and DU145 prostate cancer cells lacking OLFM4 significantly inhibited both EMT-marker expression and tumor cell growth in in vitro and in vivo models, indicating that OLFM4 may play a tumor-suppressor role in inhibiting the EMT program, as well as tumor initiation and growth, in prostate cells. Taken together, these findings suggest that OLFM4 plays an important tumor-suppressor role in prostate cancer progression and might be useful as a novel candidate biomarker for prostate cancer.

嗅觉调节蛋白4（OLFM 4）基因已被分析为肿瘤抑制基因和许多癌症中的假定生物标志物。在我们的研究中，我们分析了OLFM 4的表达与临床病理特征和与OLFM 4基因启动子区CpG位点甲基化的人原发性前列腺癌的关系。与邻近正常组织相比，前列腺癌组织中OLFM 4蛋白表达显着降低，并且在更晚期的癌症中进一步显着降低。临床数据集的生物信息学研究显示，OLFM 4 mRNA表达降低的原发性前列腺癌患者表现出较高的Gleason评分和较高的术前血清前列腺特异性抗原水平，以及较低的无复发生存率。与邻近的正常细胞相比，OLFM 4基因启动子区的8个CpG位点中的3个在癌性前列腺细胞中高甲基化，并且8个CpG位点的甲基化降低与RWPE 1和PC-3细胞中OLFM 4 mRNA表达增加相关。此外，OLFM 4基因表达的敲低与RWPE永生化正常前列腺细胞中上皮-间质转化（EMT）标记物表达的增强相关。相反，在体外和体内模型中，在缺乏OLFM 4的PC-3和DU 145前列腺癌细胞中恢复OLFM 4表达显著抑制EMT标志物表达和肿瘤细胞生长，表明OLFM 4可能在抑制前列腺细胞中的EMT程序以及肿瘤起始和生长中发挥肿瘤抑制作用。综上所述，这些发现表明OLFM 4在前列腺癌进展中起着重要的肿瘤抑制作用，并可能用作前列腺癌的新的候选生物标志物。