Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal. ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
Department of Pathology, Centro Hospitalar do Porto, Portugal.
Clin Cancer Res. 2014 Sep 15;20(18):4949-61. doi: 10.1158/1078-0432.CCR-14-0421. Epub 2014 Jul 9.
Successful therapy of patients with prostate cancer is highly dependent on reliable diagnostic and prognostic biomarkers. Brachyury is considered a negative prognostic factor in colon and lung cancer; however, there are no reports on Brachyury's expression in prostate cancer.
In this study, we aimed to assess the impact of Brachyury expression in prostate tumorigenesis using a large series of human prostate samples comprising benign tissue, prostate intraepithelial neoplasia (PIN) lesions, localized tumor, and metastatic tissues. The results obtained were compared with what can be inferred from the Oncomine database. In addition, multiple in vitro models of prostate cancer were used to dissect the biologic role of Brachyury in prostate cancer progression.
We found that Brachyury is significantly overexpressed in prostate cancer and metastatic tumors when compared with normal tissues, both at protein and at mRNA levels. Brachyury expression in the cytoplasm correlates with highly aggressive tumors, whereas the presence of Brachyury in the nucleus is correlated with tumor invasion. We found that Brachyury-positive cells present higher viability, proliferation, migration, and invasion rates than Brachyury-negative cells. Microarray analysis further showed that genes co-expressed with Brachyury are clustered in oncogenic-related pathways, namely cell motility, cell-cycle regulation, and cell metabolism.
Collectively, the present study suggests that Brachyury plays an important role in prostate cancer aggressiveness and points, for the first time, to Brachyury as a significant predictor of poor prostate cancer prognosis. Our work paves the way for future studies assessing Brachyury as a possible prostate cancer therapeutic target.
成功治疗前列腺癌患者高度依赖于可靠的诊断和预后生物标志物。Brachyury 被认为是结肠癌和肺癌的一个负预后因素；然而，目前尚无关于 Brachyury 在前列腺癌中表达的报道。
在这项研究中，我们旨在使用包含良性组织、前列腺上皮内瘤变（PIN）病变、局限性肿瘤和转移性组织的大量人类前列腺样本评估 Brachyury 表达对前列腺发生的影响。将获得的结果与 Oncomine 数据库中的推断结果进行比较。此外，还使用多种前列腺癌细胞体外模型来剖析 Brachyury 在前列腺癌进展中的生物学作用。
与正常组织相比，我们发现 Brachyury 在前列腺癌和转移性肿瘤中无论是在蛋白水平还是在 mRNA 水平都显著过表达。细胞质中的 Brachyury 表达与高度侵袭性肿瘤相关，而核内的 Brachyury 表达与肿瘤侵袭相关。我们发现 Brachyury 阳性细胞的活力、增殖、迁移和侵袭率均高于 Brachyury 阴性细胞。微阵列分析进一步表明，与 Brachyury 共表达的基因聚类在致癌相关途径中，即细胞运动、细胞周期调控和细胞代谢。
综上所述，本研究表明 Brachyury 在前列腺癌侵袭性中发挥重要作用，并首次表明 Brachyury 是前列腺癌不良预后的一个重要预测因子。我们的工作为未来评估 Brachyury 作为可能的前列腺癌治疗靶点的研究铺平了道路。
