Department of Urology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
Prostate. 2019 Apr;79(5):554-563. doi: 10.1002/pros.23761. Epub 2019 Jan 6.
HOX genes encode transcription factors that play key roles in modulating normal tissue morphogenesis, differentiation and homeostasis. Disruption of normal HOX gene expression occurs frequently in human cancers and is associated with both tumor promoting and suppressing activities. Among these is, HOXA10, a pleiotropic gene that is critical for normal prostate development. In this study we characterized HOXA10 expression in human and mouse PCa to gain insights into its clinical significance.
A meta-analysis of HOXA10 mRNA expression was carried out across several publicly available data sets. Expression of HOXA10 protein expression was assessed by immunohistochemistry (IHC) using human radical prostatectomy (RP) cases. We correlated HOXA10 expression to clinicopathological features and investigated its relationship to biochemical recurrence (BCR) after RP by the Kaplan-Meier method. HOXA10 mRNA and IHC protein expression was also examined in a mouse model of Pten-null PCa.
A meta-analysis of HOXA10 gene expression indicated dysregulated expression of HOXA10 in human PCa. IHC profiling of HOXA10 revealed inverse correlations between HOXA10 expression and Gleason pattern, Gleason score, and pathological stage (P < 0.01). Patients with low expression profiles of HOXA10 were associated with a higher risk of BCR, (OR, 3.54; 95%CI, 1.21-16.14; P = 0.049) whereas patients with high HOXA10 expression experienced longer times to BCR (P = 0.045). However, HOXA10 was not an independent predictor of BCR (OR, 1.52; 95%CI, 0.42-5.54; P = 0.52). Evaluation of expression patterns of HOXA10 in mouse prostate tumors mimicked that of humans.
Our findings show that HOXA10 expression is inversely associated with tumor differentiation and high HOXA10 expression is associated with improved BCR-free survival. This study provides human and mouse evidence to suggest tumor suppressive roles for HOXA10 in the context of prostate cancer.
HOX 基因编码转录因子，在调节正常组织形态发生、分化和内稳态方面发挥着关键作用。正常 HOX 基因表达的破坏在人类癌症中经常发生，并与促进和抑制肿瘤的活动有关。其中包括 HOXA10，这是一种多效基因，对前列腺的正常发育至关重要。在这项研究中，我们对人源和鼠源前列腺癌中的 HOXA10 表达进行了特征描述，以深入了解其临床意义。
对几个公开可用的数据集中的 HOXA10mRNA 表达进行了荟萃分析。使用人类根治性前列腺切除术 (RP) 病例通过免疫组织化学 (IHC) 评估 HOXA10 蛋白表达。我们将 HOXA10 表达与临床病理特征相关联，并通过 Kaplan-Meier 法研究其与 RP 后生化复发 (BCR) 的关系。还在 Pten 缺失型前列腺癌的小鼠模型中检查了 HOXA10mRNA 和 IHC 蛋白表达。
HOXA10 基因表达的荟萃分析表明，HOXA10 在人源前列腺癌中表达失调。HOXA10 的 IHC 分析显示，HOXA10 表达与 Gleason 模式、Gleason 评分和病理分期呈负相关 (P<0.01)。HOXA10 低表达谱的患者与 BCR 风险增加相关 (OR，3.54；95%CI，1.21-16.14；P=0.049)，而 HOXA10 高表达的患者发生 BCR 的时间更长 (P=0.045)。然而，HOXA10 不是 BCR 的独立预测因子 (OR，1.52；95%CI，0.42-5.54；P=0.52)。对小鼠前列腺肿瘤中 HOXA10 表达模式的评估与人类相似。
我们的研究结果表明，HOXA10 表达与肿瘤分化呈负相关，高 HOXA10 表达与改善 BCR 无复发生存率相关。这项研究提供了人源和鼠源证据，表明在前列腺癌中 HOXA10 具有肿瘤抑制作用。
