Olfactomedin 4 Suppresses Prostate Cancer Cell Growth and Metastasis via Negativ

嗅觉调节蛋白4(olfactomedin 4，OLFM4)基因被认为是一种抑癌基因，在许多癌症中可能是一种生物标志物。在本研究中，我们分析了人前列腺癌组织中OLFM4基因启动子区CpG甲基化与临床病理特征的关系。与邻近正常组织相比，前列腺癌组织中Olfm4蛋白的表达显著降低，在更晚期的癌症组织中进一步显着降低。临床资料的生物信息学研究表明，OLFM4表达降低的前列腺癌患者表现出更高的Gleason评分和更高的术前血清前列腺特异性抗原水平，以及更低的无复发生存率。与癌旁正常组织相比，前列腺癌组织中OLFM4基因启动子区的8个CpG位点中有3个发生高甲基化，而在RWPE1和PC-3细胞中，8个CpG位点甲基化水平的降低与OLFM4基因表达的升高有关。此外，在RWPE永生化的正常前列腺细胞中，OLFM4基因表达的下调与上皮-间充质转化(EMT)标志物的表达增强有关。相反，在缺失OLFM4的PC-3和DU145前列腺癌细胞中，恢复OLFM4的表达显著抑制了EMT标志物的表达和肿瘤细胞的生长，表明OLFM4可能在抑制EMT程序以及前列腺细胞中肿瘤的起始和生长方面起到了肿瘤抑制作用。综上所述，这些发现表明，OLFM4在前列腺癌的进展中发挥着重要的肿瘤抑制作用，并可能作为前列腺癌的一种新的候选生物标志物。

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.