Involvement of hepatocellular carcinoma biomarker, cyclase-associated protein 2 in zebrafish body development and cancer progression
Involvement of hepatocellular carcinoma biomarker, cyclase-associated protein 2 in zebrafish body development and cancer progression
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DOI：
10.1016/j.yexcr.2012.09.013
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发表时间：
2013-01-01
影响因子：
3.7
通讯作者：
Sakamoto, Michiie
中科院分区：
文献类型：
--
作者：
Effendi, Kathryn;Yamazaki, Ken;Sakamoto, Michiie
环酶相关蛋白2(CAP2)是一种在肝细胞癌中上调表达的保守蛋白。通过使用斑马鱼，结合肝癌细胞系，我们进一步研究了CAP2的作用。斑马鱼CAP2序列与人CAP2的同源性为60%，C端肌动蛋白结合区的同源性为77%，N端环化酶结合区的同源性为58%。在斑马鱼发育过程中观察到CAP2的表达，并在骨骼肌和心脏中优先表达。用两种不同的吗啉对CAP2基因敲除后，斑马鱼的体型短小，并伴有心包水肿。在斑马鱼骨骼肌中观察到CAP2与肌动蛋白共定位，在肝癌细胞系中观察到CAP2与肌动蛋白共存。在肝癌细胞系中，CAP2沉默导致片状脂体形成缺陷和细胞运动能力降低。CAP2在16例低分化肝细胞癌中有10例(63%)呈强阳性表达，在68例中分化肝细胞癌中有30例(44%)呈强阳性表达，在21例高分化肝癌中有2例(10%)呈强阳性表达。CAP2表达与肿瘤大小、分化不良、门静脉侵犯和肝内转移显著相关。我们的结果表明，CAP2在高等脊椎动物中的一个重要的保守功能可能与骨骼肌的发育过程有关。CAP2在增强细胞运动性方面也发挥了重要作用，这可能促进了肝癌进展过程中更具侵袭性的行为。这些发现突出了发育和癌症之间的联系。(C)2012 Elsevier Inc.保留所有权利。
Cyclase-associated protein 2 (CAP2) is a conserved protein that is found up-regulated in hepatocellular carcinoma (HCC). By using zebrafish, combined with HCC cell lines, we further investigated the role of CAP2. The zebrafish CAP2 sequence was 60% identical to human CAP2 with 77% homology in the C-terminal actin-binding domain, and 58% in the N-terminal cyclase-binding domain. CAP2 expression was observed during zebrafish development and was preferentially expressed in the skeletal muscle and heart. Knockdown using two different morpholinos against CAP2 resulted in a short-body morphant zebrafish phenotype with pericardial edema. CAP2 was observed co-localized with actin in zebrafish skeletal muscle, and in the leading edge of lamellipodium in HCC cell lines. CAP2 silencing resulted in a defect in lamellipodium formation and decreased cell motility in HCC cell lines. Strongly positive expression of CAP2 was observed in 10 of 16 (63%) poorly, 30 of 68 (44%) moderately, and 2 of 21 (10%) well differentiated HCC. CAP2 expression was significantly associated with tumor size, poor differentiation, portal vein invasion, and intrahepatic metastasis. Our results indicate that an important conserved function of CAP2 in higher vertebrates may be associated with the process of skeletal muscle development. CAP2 also played an important role in enhancing cell motility, which may promote a more invasive behavior in the progression of HCC. These findings highlight the link between development and cancer. (C) 2012 Elsevier Inc. All rights reserved.