title: MST4 promotes hepatocellular carcinoma epithelial-mesenchymal transition and metastasis via activation of the p-ERK pathway.
abstract: Mammalian sterile-20-like kinase 4 (MST4) has been implicated in cell proliferation and differentiation. In a previous study, we found MST4 to be an important candidate gene for metastatic hepatocellular carcinoma (HCC); however, the molecular mechanism of the promoting role of MST4 in HCC metastasis is poorly understood. In this study, we show that high expression of MST4 was detected in highly invasive HCC cells and in human HCC specimens with vascular invasion. A high level of MST4, associated with large tumor size, microvascular invasion, presence of intrahepatic metastasis, and advanced TNM classification of malignant tumors stage, was an independent prognostic factor for overall survival (P=0.004) and time to recurrence (P=0.001) after hepatectomy. Knockdown of MST4 expression in HCC cells inhibited cell proliferation, colony formation, and invasion, whereas upregulation of MST4 significantly promoted these processes by promoting epithelial-mesenchymal transition (EMT), dependent on the activation of extracellular signal-regulated protein kinase (ERK) signaling pathways. Furthermore, the combination of MST4 and phosphorylated ERK was proven to have more power to predict the outcomes of HCC patients. This study presents clinical evidence for predicting the value of MST4 in HCC overall survival and recurrence and describes the key role of MST4 in facilitating the EMT process via regulating the activation of ERK, indicating its potential role as a target for postoperative adjuvant therapy for HCC.
authors.affiliation: Liver Cancer Institute and Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China.
authors.forename: Zhen-Hai
authors.initials: ZH
authors.lastname: Lin
authors.affiliation: The Second Artillery General Hospital of Chinese People's Liberation Army, Beijing, P.R. China.
authors.forename: Liying
authors.initials: L
authors.lastname: Wang
authors.affiliation: Liver Cancer Institute and Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China.
authors.forename: Ju-Bo
authors.initials: JB
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Medical Molecular Virology (MOE and MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Liver Cancer Institute and Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China.
authors.forename: Xiao-Qiang
authors.initials: XQ
authors.lastname: Li
authors.affiliation: Liver Cancer Institute and Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Guo
authors.affiliation: Liver Cancer Institute and Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Liver Cancer Institute and Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China.
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Zhu
authors.affiliation: Liver Cancer Institute and Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China.
authors.forename: Qing-Hai
authors.initials: QH
authors.lastname: Ye
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D009362:Neoplasm Metastasis; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D000099317:Hippo Kinases
chemical_list: D014408:Biomarkers, Tumor; D017346:Protein Serine-Threonine Kinases; C430908:STK26 protein, human; D000099317:Hippo Kinases