Yang Kui, Tang Yaqiong, Iczkowski Kenneth A
Department of Pathology, University of Colorado Denver Health Science Center Aurora, Colorado, USA.
Am J Transl Res. 2010 Jan 1;2(1):88-94.
Dysregulated CD44 expression is a feature of most human cancers, including prostate cancer (PCa). PCa loses expression of CD44 standard (CD44s) which is present in benign epithelium, and overexpresses a novel splice variant isoform, CD44v7-10, specifically facilitating fibronectin binding and invasion. Naturally-occurring or synthetic phenyl-methylene hydantoin (PMH) and S-ethyl PMH (S-PMH) can reportedly augment cell-cell adhesion, and reduce invasion and growth of PCa. Benign BPH-1 and malignant PC-3M prostate cells were treated with PMH or S-PMH for 36 h and cells were harvested. Cell adhesion assays were carried out. Cancer cells' expression of total CD44 and CD44v7-10 were tested by western blot analysis and real-time RT-PCR. Compared to BPH-1 or PC-3M cells treated with vehicle only, PMH-or S-PMH-treated benign and malignant cells had decreased adhesion to hyaluronan (p=0.001 to 0.007) and fibronectin (p<0.001 to 0.047). Both compounds decreased PCa expression of CD44 total mRNA (representing mostly CD44s, to 0.076+/-0.033 and 0.254+/-0.123 of control) and CD44v7-10 (to 0.386+/-0.279 and 0.115+/-0.037 of control). S-PMH but not PMH decreased CD44 total protein, while both decreased CD44v7-10 protein. Both hydantoins lowered beta-catenin, as reported previously. Both only slightly decreased beta1-integrin, the definitive receptor for fibronectin. In conclusion, the ability of PMH and S-PMH to decrease hyaluronan adhesion appears to be mediated through decreased CD44s, while the decrease in fibronectin adhesion correlates with, and may be mediated by, decreased CD44v7-10.
CD44表达失调是包括前列腺癌（PCa）在内的大多数人类癌症的一个特征。前列腺癌会丧失良性上皮中存在的CD44标准型（CD44s）的表达，并过度表达一种新的剪接变异体亚型CD44v7-10，这特别有助于纤连蛋白结合和侵袭。据报道，天然存在的或合成的苯亚甲基乙内酰脲（PMH）和S-乙基PMH（S-PMH）可增强细胞间黏附，并减少前列腺癌的侵袭和生长。用PMH或S-PMH处理良性BPH-1和恶性PC-3M前列腺细胞36小时后收获细胞。进行细胞黏附试验。通过蛋白质免疫印迹分析和实时逆转录-聚合酶链反应检测癌细胞中总CD44和CD44v7-10的表达。与仅用赋形剂处理的BPH-1或PC-3M细胞相比，用PMH或S-PMH处理的良性和恶性细胞与透明质酸的黏附力降低（p = 0.001至0.007），与纤连蛋白的黏附力降低（p<0.001至0.047）。两种化合物均降低了前列腺癌中CD44总mRNA的表达（主要代表CD44s，降至对照的0.076±0.033和0.254±0.123）以及CD44v7-10的表达（降至对照的0.386±0.279和0.115±0.037）。S-PMH而非PMH降低了CD44总蛋白水平，而两者均降低了CD44v7-10蛋白水平。如先前报道的那样，两种乙内酰脲均降低了β-连环蛋白水平。两者仅轻微降低了β1整合素，即纤连蛋白的决定性受体。总之，PMH和S-PMH降低透明质酸黏附的能力似乎是通过降低CD44s介导的，而纤连蛋白黏附的降低与CD44v7-10的降低相关，并且可能由其介导。
