Olfactomedin 4 Suppresses Prostate Cancer Cell Growth and Metastasis via Negativ

人嗅球蛋白4基因(OLFM4)编码一种与嗅球蛋白相关的糖蛋白。Olfm4通常在包括前列腺在内的有限数量的组织中表达，但它在前列腺中的生物学功能在很大程度上是未知的。4(OLFM4)基因表达缺失与前列腺癌的高级别相关。遗传学研究发现，大约25%的人类前列腺癌样本中会发生OLFM4基因的缺失。为了探索OLFM4功能的细胞和分子机制，我们研究了Olfm4基因敲除小鼠模型和缺乏OLFM4表达的人前列腺癌细胞。对Olfm4基因敲除小鼠的前列腺表型研究发现，零星的前列腺上皮内瘤变和前列腺癌的发生与年龄有关。3个月和15个月大的Olfm4基因敲除小鼠的前列腺组织的基因表达特征显示了与前列腺癌进展相关的基因的显著变化。在Olfm4基因敲除小鼠的前列腺中，Sonic Hedgehog信号通路和靶基因显著上调。重要的是，我们发现Ofactomedin 4通过下调Hedgehog信号通路基因和靶基因的活性来抑制前列腺干/祖细胞的生长和上皮向间充质转化(EMT)。此外，我们还证明了OLFM4通过与sonic hedgehog蛋白的直接相互作用抑制了hedgehog信号通路。这些发现表明，OLFM4在前列腺癌的进展中起着关键作用，OLFM4蛋白有可能成为提高诊断/预后准确性的新标记物，并可能成为前列腺癌治疗方法的靶点。

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.