Calcium-Binding Protein 39 Promotes Hepatocellular Carcinoma Growth and Metastasis by Activating Extracellular Signal-Regulated Kinase Signaling Pathway
Calcium-Binding Protein 39 Promotes Hepatocellular Carcinoma Growth and Metastasis by Activating Extracellular Signal-Regulated Kinase Signaling Pathway
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DOI：
10.1002/hep.29312
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发表时间：
2017-11-01
期刊：
影响因子：
13.5
通讯作者：
Guan, Xin-Yuan
中科院分区：
文献类型：
--
作者：
Jiang, Lingxi;Yan, Qian;Guan, Xin-Yuan
钙结合蛋白（CAB 39）是一组不育20激酶的关键调节因子。在此，我们报道了肝细胞癌（HCC）中CAB 39的频繁上调，这与肿瘤转移（P = 0.000）、较差的无病生存率（P = 0.027）和较差的预后（P <0.000）显著相关。CAB 39在永生化人肝细胞系LO 2和肝癌细胞系QGY-7703、BEL-7402中的异位表达可增加病灶形成、软琼脂集落形成、裸鼠成瘤和细胞运动。用短发夹RNA沉默肝癌细胞系Huh 7和MHCC 97 H中的CAB 39表达，可以有效地消除其致癌功能。进一步的研究发现，CAB 39参与细胞外信号调节激酶（ERK）通路的激活，其关键位点的突变显著降低磷酸化ERK的水平。此外，CAB 39还可通过上调N-cadherin和Fibronectin，下调E-cadherin和alpha-E-catenin，促进上皮-间质转化。结果，β-连环蛋白核转位增加，其下游靶基因基质金属蛋白酶-9上调。结论：综上所述，我们的研究结果表明，CAB 39通过激活ERK信号通路在HCC的发病和进展中发挥了非常重要的致癌作用。更好地了解CAB 39可能导致其作为预后预测的生物标志物和新的治疗靶点的临床应用。
Calcium-binding protein (CAB39) is a key regulator of a group of sterile 20 kinases. Here, we report that CAB39 was frequently up-regulated in hepatocellular carcinoma (HCC), which was significantly associated with tumor metastasis (P = 0.000), poorer disease-free survival rate (P = 0.027), and poor prognosis (P 5 0.000). Ectopic expression of CAB39 in immortalized human liver cell line LO2 and HCC cell lines QGY-7703 and BEL-7402 could increase foci formation, colony formation in soft agar, tumor formation in nude mice, and cell motility. Silencing CAB39 expression in two HCC cell lines, Huh7 and MHCC97H, with short hairpin RNA could effectively abolish its oncogenic function. Further study found that CAB39 contributed to extracellular signal-regulated kinase (ERK) pathway activation, and mutations of the key sites of CAB39 markedly decrease the level of phosphorylated ERK. In addition, CAB39 could promote epithelial-mesenchymal transition by up-regulating N-cadherin and Fibronectin and down-regulating E-cadherin and alpha-E-catenin. As a result, beta-catenin nuclear translocation was increased and its downstream target gene, matrix metalloproteinase-9, was up-regulated. Conclusion: Taken together, our findings suggested that CAB39 played very important oncogenic roles in HCC pathogenesis and progression by activating the ERK signaling pathway. Better understanding of CAB39 may lead to its clinical application as a biomarker for a prognosis predictor and a novel therapeutic target.