Background:MicroRNA-379 (miR-379) has been reported to play a tumour-suppressing role in several cancer types. Our previous work demonstrated that miR-379 overexpression attenuates the metastatic spread of prostate cancer (PCa) both in vitro and in vivo. However, the underlying mechanisms remain poorly understood.Methods: To elucidate the mechanisms by which miR-379 affects metastases, we performed a cytokine array to identify secreted proteins modulated by miR-379 dysregulation in a bone microenvironment model. We then assessed the levels of the key candidate, and performed functional studies, including reporter assays, of the transcriptional regulation.Results:Prostate-specific antigen (PSA)—the clinically widely used blood biomarker for PCa—emerged as the most significantly affected secreted protein. We observed that PSA secretion increased following miR-379 inhibition and decreased with miR-379 overexpression, with parallel changes in intracellular PSA levels. However, our data suggests that miR-379 does not directly regulate PSA expression. Instead, miR-379 appears to downregulate androgen receptor (AR) expression by targeting its 3′-untranslated region (3′-UTR), thereby indirectly reducing PSA transcription through diminished AR-mediated promoter activation. Supporting this indirect mechanism, analysis of clinical samples from prostate cancer patients revealed an inverse correlation between expression of miR-379 in prostatic tissue and serum PSA levels. Furthermore, reduced miR-379 expression was associated with increased levels of AR immunostaining in malignant tissues.Conclusions: Taken together, these findings suggest that miR-379 negatively regulates PSA secretion indirectly via suppression of AR, and that the interplay between miR-379, AR, and PSA may contribute to the metastatic progression of PCa to bone.
背景：已有报道称，MicroRNA-379（miR-379）在多种癌症类型中发挥肿瘤抑制作用。我们先前的研究表明，miR-379的过表达在体外和体内均能减弱前列腺癌（PCa）的转移扩散。然而，其潜在机制尚不清楚。 方法：为阐明miR-379影响转移的机制，我们在骨微环境模型中进行了细胞因子阵列分析，以鉴定受miR-379失调调控的分泌蛋白。随后，我们评估了关键候选蛋白的水平，并进行了包括报告基因检测在内的转录调控功能研究。 结果：前列腺特异性抗原（PSA）——临床上广泛使用的前列腺癌血液生物标志物——成为受影响最显著的分泌蛋白。我们观察到，抑制miR-379后PSA分泌增加，而过表达miR-379则使其减少，细胞内PSA水平也呈现平行变化。然而，我们的数据表明，miR-379并不直接调控PSA的表达。相反，miR-379似乎通过靶向雄激素受体（AR）的3'-非翻译区（3'-UTR）来下调其表达，从而通过减弱AR介导的启动子激活来间接减少PSA的转录。支持这一间接机制的是，对前列腺癌患者临床样本的分析显示，前列腺组织中miR-379的表达与血清PSA水平呈负相关。此外，恶性组织中miR-379表达的降低与AR免疫染色水平的升高相关。 结论：综上所述，这些发现表明，miR-379通过抑制AR间接负向调控PSA的分泌，并且miR-379、AR和PSA之间的相互作用可能促进了前列腺癌向骨的转移进展。
肿瘤(癌症)患者之家