Fascin-1 expression correlates with repression of E-cadherin expression in hepatocellular carcinoma cells and augments their invasiveness in combination with matrix metalloproteinases
Fascin-1 expression correlates with repression of E-cadherin expression in hepatocellular carcinoma cells and augments their invasiveness in combination with matrix metalloproteinases
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DOI：
10.1111/j.1349-7006.2011.01910.x
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发表时间：
2011-06-01
期刊：
影响因子：
5.7
通讯作者：
Lee, Gang-Hong
中科院分区：
文献类型：
--
作者：
Hayashi, Yoshihiro;Osanai, Makoto;Lee, Gang-Hong
Fascin-1是一种肌动蛋白集束蛋白，其表达是肝细胞癌（HCC）的不良预后因素。然而，其在HCC细胞中的生物学作用仍不清楚。使用人HCC组织和细胞系HLE、Hep 3B和Huh 7，我们研究了fascin-1是否参与上皮-间质转化（EMT）并增加侵袭性，从而作为癌症侵袭性的促进剂。免疫组化分析显示，在19%的原发性肝癌中，fascin-1的表达与E-钙粘蛋白表达的抑制相关，表明EMT。在体外，HLE细胞表现出高fascin-1表达，E-钙粘蛋白的损失，并通过基质胶的有效入侵。Fascin-1的敲低显著抑制了HLE细胞的侵袭性，并轻微诱导了E-钙粘蛋白的表达。相比之下，Huh 7细胞具有低fascin-1水平，高E-cadherin表达，并且是非侵袭性的。然而，强制过表达的fascin-1只赋予适度的侵袭性，没有E-钙粘蛋白的抑制，表明单独的fascin-1不能有效地刺激侵袭性或EMT。此外，Hep 3B细胞是非侵袭性的，尽管高fascin-1表达。然而，fascin-1过表达显著增加了Huh 7细胞的迁移潜力。然后，我们评估了基质金属蛋白酶（MMPs）2和9从肝癌细胞系。MMP的分泌仅见于HLE细胞。虽然MMP水平没有升高，在fascin-1过表达Huh 7细胞，其侵袭力显着增强与HLE细胞共培养，并在MMP抑制剂的存在下被抑制。总之，我们提出，fascin-1主要作为一个迁移因子与EMT在肝癌细胞，并促进其侵袭性结合基质金属蛋白酶。（Cancer Sci 2011; 102：1228-1235）。
Expression of fascin-1, an actin bundling protein, is a poor prognostic factor in hepatocellular carcinoma (HCC). However, its biological role in HCC cells remains unclear. Using human HCC tissues and cell lines HLE, Hep3B, and Huh7, we investigated whether fascin-1 is involved in epithelial-mesenchymal transition (EMT) and increases invasiveness, thus serving as a promoter of cancer aggressiveness. Immunohistochemical analysis revealed that fascin-1 expression in 19% of primary HCCs was associated with repression of E-cadherin expression, indicating EMT. In vitro, HLE cells showed high fascin-1 expression, loss of E-cadherin, and efficient invasion through Matrigel. Knockdown of fascin-1 significantly repressed invasiveness of the HLE cells and slightly induced E-cadherin expression. In contrast, Huh7 cells had low fascin-1 levels, high E-cadherin expression, and were expectedly non-invasive. However, forced overexpression of fascin-1 conferred only modest invasiveness without E-cadherin repression, indicating that fascin-1 alone cannot effectively stimulate invasiveness or EMT. Furthermore, Hep3B cells were non-invasive despite high fascin-1 expression. Nevertheless, fascin-1 overexpression dramatically increased the migratory potential of Huh7 cells. We then evaluated matrix metalloproteinases (MMPs) 2 and 9 from the HCC cell lines. Significant MMP secretion was only found in HLE cells. Although MMP levels were not elevated in fascin-1-overexpressing Huh7 cells, their invasiveness was remarkably augmented by coculture with HLE cells, and was suppressed in the presence of an MMP inhibitor. In conclusion, we propose that fascin-1 primarily acts as a migration factor associated with EMT in HCC cells and facilitates their invasiveness in combination with MMPs. (Cancer Sci 2011; 102: 1228-1235).