Oncogenesis：揭示维生素A降低前列腺癌干细胞侵袭性机制

在一项研究中，来自英国约克大学和赫尔大学的研究人员发现维生素A能够有助于治疗和阻止前列腺癌扩散.相关研究结果于2013年4月15日在线发表在Oncogenesis期刊上，论文标题为"Retinoic acid represses invasion and stem cell phenotype by induction of the metastasis suppressors RARRES1 and LXN".

在这项研究中，研究人员发现视黄酸---由我们的饮食中的胡萝卜、绿色蔬菜和动物肝脏提供的维生素A产生的一种化学物---能够让前列腺癌干细胞(prostate cancer stem cell)中的特异性基因重新激活，从而降低这种肿瘤侵入周围组织的能力.

这些发现提示着维生素A相关化合物可能能够被用来改善对前列腺癌的临床治疗.

论文通信作者、约克大学约克郡癌症研究中心主任Norman Maitland教授说，"癌症起源于健康细胞发生差错.某些控制机制被关闭从而允许癌症生长.比如，正常的细胞获得生长和入侵周围组织的能力."

"我们发现在恶性前列腺癌干细胞中，一对特异性的基因LXN和RARRES1被关闭.当我们利用视黄酸让它们重新开启时，这种肿瘤的侵袭性降低了."基因LXN编码小鼠造血干细胞调节蛋白，即胶乳素(Latexin， LYX， 也译作羧肽酶抑制剂).基因RARRES1编码视黄酸受体应答蛋白1(retinoic acid receptor responder 1， RARRES1).LYX是已知的蛋白RARRES1的唯一同源蛋白.

Maitland教授说，"全反式视黄酸(all-trans retinoic acid)已被用来治疗另一种被称作急性前骨髓细胞性白血病(acute promyelomcytic leukaemia， APL)的癌症，并且已极其成功地提高存活率.对前列腺癌而言，我们的研究提示着视黄酸不需杀死前列腺癌干细胞，而只需将它们转化为一种更容易治疗的状态.我们的发现提示着这种化合物有望在临床上被用来治疗前列腺癌."

Maitland教授补充道，"人们多年来就已知男人血液样品中较低浓度的维生素A与前列腺癌相关联，但是没有人知道其中的相关机制.这项研究是一个振奋人心的新发展：我们饮食中的一种化合物与前列腺癌干细胞相关联."

与前列腺癌相关的拓展阅读：

• Radiother Oncol：放疗在乳腺癌和前列腺癌患者中的使用有上升趋势
• Nature Communications:前列腺癌干细胞发生DNA重排导致癌症复发
• JNCI：PSA筛查并不能预测前列腺癌特异性死亡事件的发生
• JCO:首个前列腺癌预后遗传因子
• JCO：zibotentan联合多西他赛不能改善转移性去势抵抗前列腺癌患者生存
更多信息请点击：有关前列腺癌更多资讯

doi:10.1038/oncsis.2013.6
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Retinoic acid represses invasion and stem cell phenotype by induction of the metastasis suppressors RARRES1 and LXN

E E Oldridge1, H F Walker1, M J Stower2, M S Simms3,4, V M Mann3,4, A T Collins1, D Pellacani1 and N J Maitland1

The mouse haematopoietic stem cell (SC) regulator Latexin (LXN) is the only known homologue of the retinoic acid receptor responder 1 (RARRES1) gene. Both genes lie adjacent on chromosome 3 and differ mostly by the presence of a transmembrane domain in RARRES1. Despite their homology, it is not known whether they possess similar regulatory mechanisms, cellular localization and function. Here, we identified RARRES1 and LXN as highly significantly downregulated genes in human prostate SCs, whose expression was induced by the pro-differentiation agent all-trans retinoic acid (atRA). AtRA induced expression in the most differentiated cells compared with the SC fraction, suggesting that this subpopulation was less responsive to atRA. Small interfering RNA suppression of RARRES1 and LXN enhanced the SC properties of primary prostate cultures, as shown by a significant increase in their colony-forming ability. Expression of both RARRES1 and LXN was co-ordinately repressed by DNA methylation in prostate cancer cell lines and inhibition of RARRES1 and LXN increased the invasive capacity of primary prostate cultures, which also fully rescued an inhibitory effect induced by atRA. Moreover, we showed that RARRES1 and LXN reside within different sub-cellular compartments, providing evidence that RARRES1 is not a plasma membrane protein as previously supposed but is located primarily in the endoplasmic reticulum; whereas LXN was detected in the nucleus of prostate epithelial cells. Thus, LXN and RARRES1 are potential tumour suppressor genes, which are co-ordinately regulated, SC-silenced genes functioning to suppress invasion and colony-forming ability of prostate cancer cells; yet the proteins reside within different sub-cellular compartments.nges. These results highlight that the importance of vegetation cover on soil and air temperatures.