Maelstrom Promotes Hepatocellular Carcinoma Metastasis by Inducing Epithelial-Mesenchymal Transition by Way of Akt/GSK-3β/Snail Signaling
Maelstrom Promotes Hepatocellular Carcinoma Metastasis by Inducing Epithelial-Mesenchymal Transition by Way of Akt/GSK-3β/Snail Signaling
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DOI：
10.1002/hep.26677
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发表时间：
2014-02-01
期刊：
影响因子：
13.5
通讯作者：
Guan, Xin-Yuan
中科院分区：
文献类型：
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作者：
Liu, Lulu;Dai, Yongdong;Guan, Xin-Yuan
1 q扩增是人类肝细胞癌（HCC）中最常见的染色体变异之一。在这项研究中，我们确定和表征了一个新的癌基因，大漩涡（MAEL），在1 q24。MAEL的扩增和过表达常在HCC中检测到，并与HCC复发（P = 0.031）和预后不良（P = 0.001）显著相关。功能研究表明，MAEL可促进细胞生长、迁移和裸鼠成瘤，当用短发夹RNA沉默MAEL后，上述作用均被有效抑制。进一步的研究发现MAEL可增强AKT活性，继而使GSK-3磷酸化和Snail稳定化，最终诱导上皮-间质转化（EMT），促进肿瘤的侵袭和转移。此外，MAEL在信使RNA（mRNA）水平上调多种干细胞相关基因、多药耐药基因和癌症干细胞（CSC）表面标志物。功能研究表明，MAEL的过表达增加了自我更新，化疗耐药性和肿瘤转移。结论：MAEL是一种癌基因，通过诱导EMT和增强HCC的干性，在HCC的发生和发展中起重要作用。（肝病学2014;59：531-543）
Amplification of 1q is one of the most frequent chromosomal alterations in human hepatocellular carcinoma (HCC). In this study we identified and characterized a novel oncogene, Maelstrom (MAEL), at 1q24. Amplification and overexpression of MAEL was frequently detected in HCCs and significantly associated with HCC recurrence (P = 0.031) and poor outcome (P = 0.001). Functional study demonstrated that MAEL promoted cell growth, cell migration, and tumor formation in nude mice, all of which were effectively inhibited when MAEL was silenced with short hairpin RNA (shRNAs). Further study found that MAEL enhanced AKT activity with subsequent GSK-3 phosphorylation and Snail stabilization, finally inducing epithelial-mesenchymal transition (EMT) and promoting tumor invasion and metastasis. In addition, MAEL up-regulated various stemness-related genes, multidrug resistance genes, and cancer stem cell (CSC) surface markers at the messenger RNA (mRNA) level. Functional study demonstrated that overexpression of MAEL increased self-renewal, chemoresistance, and tumor metastasis. Conclusion: MAEL is an oncogene that plays an important role in the development and progression of HCC by inducing EMT and enhancing the stemness of HCC. (Hepatology 2014;59:531-543)