Dickkopf 4 (DKK4) acts on Wnt/β-catenin pathway by influencing β-catenin in hepatocellular carcinoma
Dickkopf 4 (DKK4) acts on Wnt/β-catenin pathway by influencing β-catenin in hepatocellular carcinoma
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DOI：
10.1038/onc.2011.580
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发表时间：
2012-09-01
期刊：
影响因子：
8
通讯作者：
Luk, J. M.
中科院分区：
文献类型：
--
作者：
Fatima, S.;Lee, N. P.;Luk, J. M.
Wnt/β-连环蛋白通路的失调是包括肝细胞癌（HCC）在内的主要胃肠道癌症的标志。β-连环蛋白的致癌作用已得到明确定义，但其在肝癌中积累的原因仍不清楚。Dickkopf 4（DKK 4）是Wnt/β-catenin信号通路的负调控因子，但其在肝癌发生中的作用尚不清楚。我们研究了DKK 4在HCC中β-连环蛋白调节中的作用。真实的时间定量PCR检测发现47%（38/81）的HCC中DKK 4表达降低。DKK 4在两种HCC细胞系PLC/PRF/5（PLC）和MHCC 97 L（97 L）中的异位表达减弱了β-连环蛋白反应性荧光素酶活性，并降低了β-连环蛋白和细胞周期蛋白D1蛋白水平。为了研究DKK 4对肝癌细胞生长和致瘤性的影响，我们从PLC和97 L细胞中建立了两个稳定的肝癌细胞系。功能分析表明，DKK 4的过表达阻碍细胞增殖，减少集落形成和延迟细胞迁移。当使用表达DKK 4的97 L稳定细胞在裸鼠中诱导肿瘤异种移植物时（n = 8），观察到肿瘤尺寸减小（P = 0.027）。此外，免疫组化研究表明，DKK 4表达减少与HCC组织中β-连环蛋白的积累有关。此外，在表达DKK 4的97 L稳定细胞中使用特异性抑制剂抑制蛋白酶体掩盖了β-连环蛋白的作用。我们的研究结果表明DKK 4的潜在肿瘤抑制作用以及HCC的重要调节因子。Oncogene（2012）31，4233-4244; doi：10.1038/onc.2011.580; 2012年1月16日在线发表
Deregulation of Wnt/beta-catenin pathway is a hallmark of major gastrointestinal cancers including hepatocellular carcinoma (HCC). The oncogenic role of beta-catenin is well defined but reasons for its accumulation in HCC remain unclear. Dickkopf 4 (DKK4) acts as a negative regulator of Wnt/beta-catenin pathway but its functional role in liver carcinogenesis has not been studied. We investigated the role of DKK4 in beta-catenin regulation in HCC. Reduced expression of DKK4 was found in 47% (38/81) of HCC, as measured by quantitative real time PCR. Ectopic expression of DKK4 in two HCC cell lines, PLC/PRF/5 (PLC) and MHCC97L (97L), attenuated beta-catenin responsive luciferase activity, and decreased both beta-catenin and cyclin D1 protein levels. To study the effect of DKK4 on cell growth and tumourigenicity, two stable HCC cell lines were established from PLC and 97L cells. Functional assays demonstrated that overexpression of DKK4 hampered cell proliferation, reduced colony formation and retarded cell migration. When DKK4-expressing 97L stable cells were used to induce tumour xenografts in nude mice (n = 8), reduction in tumour sizes was observed (P = 0.027). Furthermore, immunohistochemical studies showed that decreased expression of DKK4 was associated with beta-catenin accumulation in HCC tissues. Additionally, inhibition of the proteasome using specific inhibitor in DKK4-expressing 97L stable cells masked the effect of beta-catenin. Our findings suggest a potential tumour suppressive role of DKK4 as well as that of an important regulator of HCC. Oncogene (2012) 31, 4233-4244; doi:10.1038/onc.2011.580; published online 16 January 2012