L-type amino acid transporter 1 as a potential molecular target in human astrocytic tumors
L-type amino acid transporter 1 as a potential molecular target in human astrocytic tumors
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DOI：
10.1002/ijc.21866
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发表时间：
2006-08-01
影响因子：
6.4
通讯作者：
Endou, Hitoshi
中科院分区：
文献类型：
--
作者：
Nawashiro, Hiroshi;Otani, Naoki;Endou, Hitoshi
L型氨基酸转运体1(LAT1)是一种Na+非依赖性的中性氨基酸转运体，对大分子中性氨基酸的转运起着至关重要的作用。LAT1已被鉴定为C6胶质瘤细胞CD98异源二聚体的轻链。LAT1也对应于TA1，TA1是一种主要在胎儿组织和癌细胞中表达的癌胎儿抗原。我们首次研究了该转运蛋白在60例人原发星形细胞肿瘤组织中的表达。LAT1是独一无二的，因为它需要一个额外的单膜跨越蛋白，即4F2细胞表面抗原的重链(4F2hc)，才能实现其功能表达。4F2hc的表达采用免疫组织化学方法检测。Kaplan-Meier分析表明，在整个研究组(p<；0.0001)，尤其是多形性胶质母细胞瘤患者(p=0.0001)，LAT1的高表达与较差的存活率相关。COX回归分析表明，LAT1的表达是预后的显著预测因素之一，与所有其他变量无关。在此基础上，我们还利用大鼠C6胶质瘤模型，研究了LAT1的特异性抑制剂2-氨基双环-2(2，2，1)-庚烷-2-羧酸(BCH)对C6胶质瘤细胞存活的影响。BCH在体内外均能抑制C6胶质瘤细胞的生长，并呈剂量依赖关系。经BCH治疗的大鼠Kaplan-Meier生存数据有显著意义。这些发现提示LAT1可能是胶质瘤治疗的分子靶点之一。(C)2006年Wiley-Liss，Inc.
L-type amino acid transporter 1 (LAT1) is a Na+-independent neutral amino acid transport agency and essential for the transport of large neutral amino acids. LAT1 has been identified as a light chain of the CD98 heterodimer from C6 glioma cells. LAT1 also corresponds to TA1, an oncofetal antigen that is expressed primarily in fetal tissues and cancer cells. We have investigated for the first time, the expression of the transporter in the human primary astrocytic tumor tissue from 60 patients. LAT1 is unique because it requires an additional single membrane spanning protein, the heavy chain of 4F2 cell surface antigen (4F2hc), for its functional expression. 4F2hc expression was also determined by immunuhistochemistry. Kaplan-Meier analyses demonstrated that high LAT1 expression correlated with poor survival for the study group as a whole (p < 0.0001) and for those with glioblastoma multiforme in particular (p = 0.0001). Cox regression analyses demonstrated that LAT1 expression was one of significant predictors of outcome, independent of all other variables. On the basis of these findings, we also investigated the effect of the specific inhibitor to LAT1, 2-aminobicyclo-2 (2,2,1)-heptane-2-carboxylic acid (BCH), on the survival of C6 glioma cells in vitro and in vivo using a rat C6 glioma model. BCH inhibited the growth of C6 glioma cells in vitro and in vivo in a dose-dependent manner. Kaplan-Meier survival data of rats treated with BCH were significant. These findings suggest that LAT1 could be one of the molecular targets in glioma therapy. (c) 2006 Wiley-Liss, Inc.