CUL4A facilitates hepatocarcinogenesis by promoting cell cycle progression and epithelial-mesenchymal transition.
CUL4A facilitates hepatocarcinogenesis by promoting cell cycle progression and epithelial-mesenchymal transition.
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CUL4A通过促进细胞周期进程和上皮间质转化促进肝癌发生
DOI：
10.1038/srep17006
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发表时间：
2015-11-23
影响因子：
4.6
通讯作者：
Liang X
中科院分区：
文献类型：
--
作者：
Pan Y;Wang B;Yang X;Bai F;Xu Q;Li X;Gao L;Ma C;Liang X
CUL 4A是CULLIN家族的成员，作为E3泛素连接酶的支架蛋白发挥功能。据报道，CUL 4A基因在人原发性肝细胞癌（HCC）中有扩增现象。然而，CUL 4A在HCC中的确切作用仍然未知。本研究旨在探讨CUL 4A在肝癌发生发展中的表达及功能。通过免疫组化研究，我们发现CUL 4A在HCC组织中表达增加。统计学分析显示，CUL 4A表达与肿瘤分化程度和患者生存率呈负相关，但与肝细胞增殖以及淋巴和静脉浸润呈正相关。HCC组织中CUL 4A的表达与患者的HBeAg状态相关，并且在HCC细胞系中被HBV上调。进一步的功能检测显示，CUL 4A过表达显著促进BALB/c小鼠H22肿瘤同种移植物的生长。CUL 4A基因敲低抑制肝癌细胞的增殖，并伴有S期细胞减少和Cyclin A和Cyclin B1的抑制。此外，CUL 4A siRNA改善了HCC细胞系的运动性，改变了上皮间质转化（EMT）相关分子的表达。综上所述，我们的研究结果表明，CUL 4A在HCC的进展中起着关键作用，并可能作为一个潜在的临床诊断和治疗靶点的标志物。
CUL4A, a member of the CULLIN family, functions as a scaffold protein for an E3 ubiquitin ligase. It was reported that theCUL4Agene showed amplification in some human primary hepatocellular carcinomas (HCC). However, the exact role of CUL4A in HCC remains unknown. Here, we aimed to investigate the expression and function of CUL4A in HCC development. Through immunohistochemistry study, we showed increased CUL4A expression in HCC tissues. Statistical analysis disclosed an inverse correlation between CUL4A expression and tumor differentiation grade and patient survival, but a positive correlation with hepatocyte proliferation as well as lymphatic and venous invasion. CUL4A expression in HCC tissues was associated with HBeAg status in patients and upregulated by HBV in HCC cell lines. Further functional assay showed that CUL4A overexpression significantly promoted growth of H22 tumor homografts in BALB/c mice. Consistently, CUL4A knockdown inhibited the proliferation of established HCC cells, accompanied by S-phase reduction and Cyclin A and Cyclin B1 repression. Furthermore, CUL4A siRNA ameliorated the motility of HCC cell lines with altered expression of epithelial-mesenchymal transition (EMT)-associated molecules. Taken together, our findings indicate that CUL4A plays a pivotal role in HCC progression and may serve as a potential marker for clinical diagnosis and target for therapy.