Calcium‐binding protein 39 promotes hepatocellular carcinoma growth and metastasis by activating extracellular signal‐regulated kinase signaling pathway

摘要

Calciumbinding protein (CAB39 ) is a key regulator of a group of sterile 20 kinases. Here, we report thatCAB39 was frequently upregulated in hepatocellular carcinoma (HCC), which was significantly associated with tumor metastasis (P = 0.000), poorer diseasefree survival rate (P = 0.027), and poor prognosis (P = 0.000). Ectopic expression ofCAB39 in immortalized human liver cell line LO2 and HCC cell lines QGY7703 and BEL7402 could increase foci formation, colony formation in soft agar, tumor formation in nude mice, and cell motility. SilencingCAB39 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 signalregulated kinase (ERK) pathway activation, and mutations of the key sites of CAB39 markedly decrease the level of phosphorylated ERK. In addition, CAB39 could promote epithelialmesenchymal transition by upregulating Ncadherin and Fibronectin and downregulating Ecadherin and ?Ecatenin. As a result, ?catenin nuclear translocation was increased and its downstream target gene, matrix metalloproteinase9, was upregulated.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. (Hepatology 2017;66:15291545).