Olfactomedin 4 Suppresses Prostate Cancer Cell Growth and Metastasis via Negativ

人类嗅消素4基因（OLFM4）编码一种与嗅消素相关的糖蛋白。OLFM4通常在包括前列腺在内的有限组织中表达，但其在前列腺中的生物学功能在很大程度上是未知的。olfactomedin 4 （OLFM4）基因表达缺失与人类高级别前列腺癌相关。遗传学研究发现，大约25%的人类前列腺癌样本中存在嗅去蛋白4 （OLFM4）基因缺失。为了探索OLFM4功能的细胞和分子机制，我们研究了OLFM4敲除小鼠模型和缺乏OLFM4表达的人前列腺癌细胞。对olfm4基因敲除小鼠进行的前列腺表型研究发现，偶尔发生的前列腺上皮内瘤变和前列腺腺癌以年龄依赖的方式发生。olfm4基因敲除小鼠在3月龄和15月龄时前列腺组织的基因表达特征显示，与前列腺肿瘤进展相关的基因发生了显著变化。olfm4敲除小鼠前列腺中Sonic刺猬信号通路和靶基因显著上调。重要的是，我们发现Olfactomedin 4通过下调刺猬信号通路基因和靶基因活性抑制前列腺干细胞/祖细胞生长和上皮-间质转化（EMT）。此外，我们证明OLFM4通过与sonic hedgehog蛋白的直接相互作用抑制hedgehog信号通路。这些发现表明OLFM4在前列腺肿瘤进展中起着关键作用，OLFM4蛋白有潜力作为提高前列腺癌诊断/预后准确性的新标记物和治疗方法的可能靶点。

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.