title: 14-3-3η is a novel growth-promoting and angiogenic factor in hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The continued search for novel therapeutic strategies for HCC is urgently required. In this study, we aimed to investigate the functions and clinical significance of 14-3-3η protein in HCC.
  
  
  
  Expressions of genes and proteins were determined by quantitative reverse transcription polymerase chain reaction, Western blot, and immunohistochemistry. Their functions were assessed by endothelial cell recruitment, tube formation, wound healing, flow cytometry, immunostaining, immunoprecipitation, and xenograft assay. A tissue microarray followed by univariate and multivariate analyses was performed to indicate the clinical significance.
  
  
  
  In HCC specimens, overexpression of 14-3-3η was observed not only in tumors but also in intratumoral vessels. In HCC and vascular endothelial cells, 14-3-3η stimulated proliferation and angiogenesis, but attenuated the functions of sorafenib. Briefly, 14-3-3η facilitated the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2). Then, by binding to the phosphorylated-ERK1/2 (p-ERK1/2), formed a functional positive feed-back loop. A xenograft model showed that, blockage of either 14-3-3η or ERK1/2 inhibited the tumor growth. Finally, tissue microarray analyses showed that overexpression of 14-3-3η, either in tumors or intratumoral vessels, contributed to the poor survival.
  
  
  
  The 14-3-3η-ERK1/2 feedback loop played a characteristic growth-promoting role in HCC, not only in tumors but also in intratumoral vessels. Further, 14-3-3η could be a potential therapeutic target for HCC and a biomarker for predicting sorafenib treatment response.
  
  
  
  Here we found that, 14-3-3η protein exhibited a characteristic growth-promoting effect in both tumor and intratumoral vessels of hepatocellular carcinoma by interacting with ERK1/2 signaling.
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital, Nanjing Medical University, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Jiang
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Medical Center for Digestive Diseases, The Second Affiliated Hospital, Nanjing Medical University, China.
authors.forename: Guangming
authors.initials: G
authors.lastname: Huang
authors.affiliation: Department of Medical Center for Digestive Diseases, The Second Affiliated Hospital, Nanjing Medical University, China.
authors.forename: Fuxing
authors.initials: F
authors.lastname: Pu
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital, Nanjing Medical University, China.
authors.forename: Qinqiang
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital, Nanjing Medical University, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Ju
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital, Nanjing Medical University, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital, Nanjing Medical University, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital, Nanjing Medical University, China.
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital, Nanjing Medical University, China.
authors.forename: Xiagang
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital, Nanjing Medical University, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Chengyu
authors.initials: C
authors.lastname: Jiao
authors.affiliation: Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Xiangcheng
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, China. Electronic address: liyuan@njmu.edu.cn.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital, Nanjing Medical University, China. Electronic address: zjpnjmu@hotmail.com.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhang
mesh_terms: D043925:Angiogenesis Inducing Agents; D006528:Carcinoma, Hepatocellular; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms; D009389:Neovascularization, Pathologic
chemical_list: D043925:Angiogenesis Inducing Agents
keywords: 14-3-3η; Angiogenesis; Extracellular signal-regulated kinase1/2; Hepatocellular carcinoma; Tumor growth