Aberrantly activated Gli2-KIF20A axis is crucial for growth of hepatocellular carcinoma and predicts poor prognosis.
Aberrantly activated Gli2-KIF20A axis is crucial for growth of hepatocellular carcinoma and predicts poor prognosis.
复制标题
异常激活的 Gli2-KIF20A 轴对于肝细胞癌的生长至关重要并预测不良预后
DOI：
10.18632/oncotarget.8441
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发表时间：
2016-05-03
期刊：
影响因子：
--
通讯作者：
Luo S
中科院分区：
文献类型：
--
作者：
Shi C;Huang D;Lu N;Chen D;Zhang M;Yan Y;Deng L;Lu Q;Lu H;Luo S
胶质瘤相关癌基因2（Gli 2）是Hedgehog（Hh）信号的主要转录调节因子，对肝细胞癌（HCC）的生长和生存至关重要。然而，Gli 2在人HCC中的潜在分子机制和关键下游靶点尚未完全了解。在这里，我们报告了驱动蛋白家族成员20 A（KIF 20 A）作为Gli 2的新下游靶点的鉴定，Gli 2对HCC增殖和肿瘤生长很重要。Hh信号的抑制导致HCC细胞中KIF 20 A表达的显著降低，而Gli 2的过表达通过激活叉头盒M1（FoxM 1）-MMB复合物介导的该驱动蛋白基因的转录来升高KIF 20 A表达。Gli 2诱导的HCC细胞生长需要KIF 20 A的增强表达，并且Gli 2或KIF 20 A的敲低在体外和体内抑制HCC细胞的增殖。与这些结果相关，临床HCC样本的分析表明，Gli 2，FoxM 1和KIF 20 A在原发性HCC样本中高度升高，并代表HCC复发和生存的重要风险因素。结论：KIF 20 A是Hh信号转导的重要下游靶基因。而且，Gli 2-KIF 20 A轴对于人HCC细胞的增殖和生长至关重要。我们的研究还表明Gli 2-KIF 20 A轴作为未来治疗干预的潜在靶点，并作为HCC的独立预后生物标志物。
Glioma-associated oncogene 2 (Gli2), a primary transcriptional regulator of Hedgehog (Hh) signaling, is essential for hepatocellular carcinoma (HCC) growth and survival. However, the underlying molecular mechanism and crucial downstream targets of Gli2 in human HCC are not fully understood. Here, we report the identification of kinesin family member 20A (KIF20A) as a novel downstream target of Gli2, which is important for HCC proliferation and tumor growth. Inhibition of Hh signaling leads to a remarkable decrease of KIF20A expression in HCC cells, whereas overexpression of Gli2 elevates KIF20A expression by activating Forkhead Box M1 (FoxM1)-MMB complex-mediated transcription of this kinesin gene. Gli2-induced HCC cell growth requires enhanced expression of KIF20A, and knockdown of Gli2 or KIF20A represses the proliferation of HCC cells in vitro and in vivo. Correlated with these results, analyses of clinical HCC samples show that Gli2, FoxM1 and KIF20A are highly elevated in primary HCC samples and represent significant risk factors for HCC recurrence and survival. Conclusion: KIF20A is an important downstream target gene of Hh signaling. And, the Gli2-KIF20A axis is essential for the proliferation and growth of human HCC cells. Our study also suggests Gli2-KIF20A axis as a potential target for future therapeutic intervention and as an independent prognostic biomarker for HCC.
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DOI：
10.1016/j.bbagrm.2012.03.008
发表时间：
2012-08-01
影响因子：
4.7
作者：
Down, Christin F.;Millour, Julie;Watson, Roger J.
通讯作者：
Watson, Roger J.
影响因子：
6
作者：
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Sobczak-Thepot, Joelle
影响因子：
14.9
作者：
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通讯作者：
Engeland K
影响因子：
11.4
作者：
Hill, E;Clarke, N;Barr, FA
通讯作者：
Barr, FA
影响因子：
5.8
作者：
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通讯作者：
Werner, T