DKK1 promotes hepatocellular carcinoma cell migration and invasion through β-catenin/MMP7 signaling pathway.
DKK1 promotes hepatocellular carcinoma cell migration and invasion through β-catenin/MMP7 signaling pathway.
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DOI：
10.1186/1476-4598-12-157
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发表时间：
2013-12-10
期刊：
影响因子：
37.3
通讯作者：
Xie SQ
中科院分区：
文献类型：
--
作者：
Chen L;Li M;Li Q;Wang CJ;Xie SQ
近期有若干报道表明，DKK1的高表达与肝细胞癌（HCC）的进展密切相关。然而，DKK1在HCC中的生物学功能尚未得到充分记录。
在本研究中，利用MTT法、集落形成实验、划痕实验、Transwell实验以及人HCC样本，对DKK1在肿瘤细胞增殖、迁移和侵袭中的作用进行了研究。
功能获得和功能缺失研究均表明，DKK1不影响肿瘤细胞增殖和集落形成，但显著促进了HCC细胞的迁移和侵袭。后续研究显示，β - 连环蛋白是DKK1的一个重要靶点。通过药物抑制剂阻断β - 连环蛋白可拮抗DKK1的功能，而通过质粒转染引入β - 连环蛋白或用GSK3β抑制剂处理则模拟了DKK1的促迁移和促侵袭效应。我们进一步揭示，DKK1至少部分通过促进β - 连环蛋白表达，进而上调基质金属蛋白酶7（MMP7）的表达来发挥其促侵袭功能，这一过程独立于经典的Wnt信号通路。此外，引入MMP7显著增强了HCC细胞在体外侵袭细胞外基质凝胶的能力。一致地，在人HCC组织中，DKK1水平与β - 连环蛋白表达以及肿瘤转移呈正相关。
综上所述，这些结果表明DKK1在HCC中过表达；此外，异位表达的DKK1至少部分通过β - 连环蛋白/MMP7信号轴促进HCC细胞迁移和侵袭，这提示DKK1可能是HCC治疗的一个有前景的靶点。
Recently several reports have indicated that elevated expression of DKK1 is tightly associated with the progression of hepatocellular carcinoma (HCC). However, the biological function of DKK1 in HCC has not yet been well documented. In this study, the role of DKK1 in tumor cell proliferation, migration and invasion was investigated using MTT, colony formation, wound scratch, transwell assays, and also human HCC samples. Both gain- and loss-of-function studies showed that DKK1 did not influence the tumor cell proliferation and colony formation, while dramatically promoted HCC cell migration and invasion. Subsequent investigations revealed that β-catenin was an important target of DKK1. The blocking of β-catenin by pharmacological inhibitor antagonized the function of DKK1, whereas introduction of β-catenin by transfection with plasmids or treatment with GSK3β inhibitor phenocopied the pro-migration and pro-invasion effects of DKK1. We further disclosed that DKK1 exerted its pro-invasion function, at least in part, by promoting β-catenin expression, in turn, upregulating the expression of matrix metalloproteinase 7 (MMP7), which was independent of the canonical Wnt signaling pathway. Moreover, introduction of MMP7 significantly enhanced the ability of HCC cells to invade extracellular matrix gel in vitro. Consistently, in human HCC tissues, DKK1 level was positively correlated with β-catenin expression, as well as tumor metastasis. Taken together, these results demonstrated that DKK1 is overexpressed in HCC; moreover, ectopic expression DKK1 promotes HCC cell migration and invasion at least partly through β-catenin/MMP7 signaling axis, suggesting that DKK1 may be a promising target for HCC therapy.
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