The microtubule-associated protein PRC1 promotes early recurrence of hepatocellular carcinoma in association with the Wnt/β-catenin signalling pathway.
The microtubule-associated protein PRC1 promotes early recurrence of hepatocellular carcinoma in association with the Wnt/β-catenin signalling pathway.
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DOI：
10.1136/gutjnl-2015-310625
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发表时间：
2016-09
期刊：
影响因子：
24.5
通讯作者：
Hui KM
中科院分区：
文献类型：
--
作者：
Chen J;Rajasekaran M;Xia H;Zhang X;Kong SN;Sekar K;Seshachalam VP;Deivasigamani A;Goh BK;Ooi LL;Hong W;Hui KM
肝细胞癌（HCC）是全球范围内癌症死亡的第二大原因。已在肝癌中观察到微管相关蛋白（MAP）的变化。然而，这些改变的机制仍然知之甚少。我们的目的是研究MAP蛋白质胞质分裂调节因子1（PRC 1）在肝癌发生和早期肝癌复发中的作用。通过微阵列、免疫印迹和免疫组化分析评估HCC样品中PRC 1的表达。利用siRNA介导的和慢病毒载体介导的基因敲除等分子和细胞技术研究PRC 1的功能和机制。PRC 1表达与早期HCC复发和患者预后不良相关。在HCC中，PRC 1通过促进癌细胞增殖、干性、转移和肿瘤发生而发挥致癌作用。我们进一步证明PRC 1的表达和分布受Wnt 3a信号传导的动态调节。PRC 1敲低损害转录因子（TCF）的转录活性，降低Wnt靶蛋白的表达和降低核β-连环蛋白水平。在机制上，PRC 1与β-连环蛋白破坏复合物相互作用，调节Wnt 3a诱导的该破坏复合物的膜隔离，抑制腺瘤性结肠息肉病（APC）稳定性并促进β-连环蛋白从APC复合物释放。在体内，PRC 1高表达与核β-连环蛋白和Wnt靶点表达相关。PRC 1作为一组48个先前确定的Wnt调控的肝癌复发相关基因（WRRAG）的主调节因子。因此，PRC 1通过Wnt信号传导控制WRRAG如FANCI、SPC 25、KIF 11和KIF 23的表达和功能。我们确定PRC 1是一种新的Wnt靶点，它在一个正反馈回路中发挥作用，该回路加强Wnt信号传导，促进早期HCC复发。
Hepatocellular carcinoma (HCC) is the second leading cause of cancer mortality worldwide. Alterations in microtubule-associated proteins (MAPs) have been observed in HCC. However, the mechanisms underlying these alterations remain poorly understood. Our aim was to study the roles of the MAP protein regulator of cytokinesis 1 (PRC1) in hepatocarcinogenesis and early HCC recurrence. PRC1 expression in HCC samples was evaluated by microarray, immunoblotting and immunohistochemistry analysis. Molecular and cellular techniques including siRNA-mediated and lentiviral vector-mediated knockdown were used to elucidate the functions and mechanisms of PRC1. PRC1 expression was associated with early HCC recurrence and poor patient outcome. In HCC, PRC1 exerted an oncogenic effect by promoting cancer proliferation, stemness, metastasis and tumourigenesis. We further demonstrated that the expression and distribution of PRC1 is dynamically regulated by Wnt3a signalling. PRC1 knockdown impaired transcription factor (TCF) transcriptional activity, decreased Wnt target expression and reduced nuclear β-catenin levels. Mechanistically, PRC1 interacts with the β-catenin destruction complex, regulates Wnt3a-induced membrane sequestration of this destruction complex, inhibits adenomatous polyposis coli (APC) stability and promotes β-catenin release from the APC complex. In vivo, high PRC1 expression correlated with nuclear β-catenin and Wnt target expression. PRC1 acted as a master regulator of a set of 48 previously identified Wnt-regulated recurrence-associated genes (WRRAGs) in HCC. Thus, PRC1 controlled the expression and function of WRRAGs such as FANCI, SPC25, KIF11 and KIF23 via Wnt signalling. We identified PRC1 as a novel Wnt target that functions in a positive feedback loop that reinforces Wnt signalling to promote early HCC recurrence.
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影响因子：
13.5
作者：
Gao, Wei;Kim, Heungnam;Feng, Mingqian;Phung, Yen;Xavier, Charles P.;Rubin, Jeffrey S.;Ho, Mitchell
通讯作者：
Ho, Mitchell
影响因子：
11.2
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通讯作者：
Golub TR
影响因子：
13.5
作者：
Llovet, Josep M.;Bruix, Jordi
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Bruix, Jordi
影响因子：
29.4
作者：
Laurent-Puig, P;Legoix, P;Zucman-Rossi, J
通讯作者：
Zucman-Rossi, J
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影响因子：
13.5
作者：
Li, Li;Jin, Ronghua;Chen, Dexi
通讯作者：
Chen, Dexi