Ectopic overexpression of filamin C scaffolds MEK1/2 and ERK1/2 to promote the progression of human hepatocellular carcinoma
Ectopic overexpression of filamin C scaffolds MEK1/2 and ERK1/2 to promote the progression of human hepatocellular carcinoma
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丝蛋白C支架MEK1/2和ERK1/2的异位过度表达促进人肝细胞癌的进展
DOI：
10.1016/j.canlet.2016.11.037
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发表时间：
2017
期刊：
影响因子：
9.7
通讯作者：
Li Yongmei
中科院分区：
文献类型：
--
作者：
Yang Baicai;Liu Yun;Zhao Jie;Hei Kaiwen;Zhuang Hao;Li Qiang;Wei Wen;Chen Ruibing;Zhang Ning;Li Yongmei
肝细胞癌（HCC）的侵袭和转移是由复杂的信号转导网络和下游的细胞骨架和粘附分子介导的。在这项研究中，一项基于微阵列的分析显示，在两种转移性HCC细胞系MHCC97L和HCCLM3中，丝蛋白C （FLNC）显著增加，而FLNC通常在肌肉中表达，而不是在肝细胞中表达。临床病理研究表明，FLNC表达升高与微血管侵袭及预后不良有关。在HCC细胞系和患者肿瘤样本中，FLNC启动子区域存在特异性低甲基化，这可能是FLNC异位过表达的原因。FLNC下调抑制细胞迁移，抑制细胞增殖，促进细胞凋亡。机制研究表明，FLNC与丝裂原激活的细胞外信号调节激酶1/2 （MEK1/2）和细胞外信号调节激酶1/2 （ERK1/2）相互作用，FLNC下调可抑制MEK1/2和ERK1/2的激活。裸鼠异种肿瘤移植实验进一步证实了FLNC在HCC进展和转移中的作用。我们的研究结果揭示了细胞骨架蛋白FLNC在肿瘤发生过程中增强丝裂原激活的蛋白激酶信号通路的新机制。
Hepatocellular carcinoma (HCC) invasion and metastasis are mediated by a complicated signal transduction network and downstream cytoskeletal and adhesion molecules. In this study, a microarray-based analysis revealed a dramatic increase in filamin C (FLNC), which is commonly expressed in muscle rather than in liver cells, in the two metastatic HCC cell lines MHCC97L and HCCLM3. Clinicopathological studies showed that increased FLNC expression was associated with microvascular invasion and poor prognosis. Specific hypomethylation was identified within the FLNC promoter region in HCC cell lines and patient tumor samples, which might contribute to the ectopic overexpression of FLNC. FLNC downregulation inhibited cell migration and impaired cell proliferation and promoted apoptosis. Mechanistic studies suggested that FLNC interacts with mitogen-activated extracellular signal-regulated kinase 1/2 (MEK1/2) and extracellular signal-regulated kinase 1/2 (ERK1/2) and that FLNC downregulation inhibited MEK1/2 and ERK1/2 activation. Xenographic tumor transplantation experiments in nude mice further confirmed the role of FLNC in HCC progression and metastasis. Our results reveal a novel mechanism by which the cytoskeletal protein FLNC enhances the mitogen-activated protein kinase signaling pathway during tumorigenesis.