Department of Anatomy, Chonnam National University Medical School, Gwangju, Korea.
Department of Urology, Chonnam National University Medical School, Gwangju, Korea.
Oncogene. 2014 Sep 11;33(37):4558-67. doi: 10.1038/onc.2013.404. Epub 2013 Oct 7.
Characteristically, prostate cancer (PCa) cells exhibit marked decrease in intracellular zinc; however, the mechanism responsible is not clearly understood. HOXB13 is involved in PCa progression and is overexpressed in castration-resistant PCa. DNA microarray analysis of LNCaP Pca cells showed that ZnT zinc output transporters were strikingly upregulated among androgen-independent HOXB13 target genes. Furthermore, exogenous HOXB13 caused intracellular zinc concentrations to fall in PCa cells, stimulated NF-κB-mediated signaling by reducing inhibitor of NF-κB alpha (IκBα) and enhanced the nuclear translocation of RelA/p65. Human prostate tumors also exhibited strong inverse correlation between the protein expressions of HOXB13 and IκBα. Consequently, HOXB13 stimulated PCa cell invasion, and this was inhibited by the suppression of ZnT4. In addition, studies in a PC3 orthotopic mouse model of PCa metastasis showed that HOXB13 is a strong metastatic stimulator. Taken together, these results show that HOXB13 promotes PCa invasion and metastasis by decreasing intracellular zinc levels, thus stimulating NF-κB signals, and suggest that HOXB13 acts as a modulator of intracellular zinc levels that promotes the malignant characteristics of PCa.
前列腺癌细胞表现出明显的细胞内锌含量降低，然而，其负责的机制尚不清楚。HOXB13 参与前列腺癌的进展，并且在去势抵抗性前列腺癌中过表达。LNCaP Pca 细胞的 DNA 微阵列分析表明，ZnT 锌输出转运体在雄激素非依赖性 HOXB13 靶基因中显著上调。此外，外源性 HOXB13 导致前列腺癌细胞内锌浓度降低，通过减少 NF-κBα 抑制剂（IκBα）来刺激 NF-κB 介导的信号，并增强 RelA/p65 的核转位。人类前列腺肿瘤也表现出 HOXB13 和 IκBα 蛋白表达之间的强烈负相关。因此，HOXB13 刺激前列腺癌细胞侵袭，而 ZnT4 的抑制可抑制这种侵袭。此外，在前列腺癌转移的 PC3 原位小鼠模型中的研究表明，HOXB13 是一种强烈的转移刺激物。总之，这些结果表明，HOXB13 通过降低细胞内锌水平来促进前列腺癌的侵袭和转移，从而刺激 NF-κB 信号，表明 HOXB13 作为细胞内锌水平的调节剂，促进前列腺癌的恶性特征。
