title: DDR2 facilitates hepatocellular carcinoma invasion and metastasis via activating ERK signaling and stabilizing SNAIL1.
abstract: BACKGROUND
  Several studies have found that DDR2 is up-regulated in many tumor types and facilitates tumor progression. However, the role of DDR2 in hepatocellular carcinoma (HCC) progression and its downstream signaling pathways remain unclear.
  
  
  METHODS
  DDR2 expression was assessed in several cell lines and 112 pairs of HCC and matched adjacent noncancerous liver tissues. Clinical significance of DDR2 in HCC was analyzed. Phosphorylated DDR2 (p-DDR2) expression was detected by immunoblotting to evaluate its correlation with DDR2. The effect of DDR2 on HCC cell migration and invasion were examined. Cycloheximide chase experiments were performed to detect the half-life of SNAIL1. Moreover, DDR2 expression was detected by immunohistochemistry to evaluate its correlation with SNAIL1. The regulatory effect of DDR2 on ERK signaling, SNAIL1, EMT, MT1-MMP and MMP2 was confirmed by immunoblotting. The effect of type I collagen on DDR2/ERK2/SNAIL1 signaling was assessed.
  
  
  RESULTS
  DDR2 was more highly expressed in HCC than in non-HCC tissues. DDR2 overexpression was correlated with clinicopathological features of poor prognosis. Clinical analysis revealed that DDR2 is an independent prognostic marker for predicting overall survival and disease free survival of HCC patients. Overexpression of DDR2 is associated with p-DDR2 amplification. In vitro studies showed that DDR2 facilitates HCC cell invasion, migration and EMT via activating ERK2 and stabilizing SNAIL1. DDR2 can up-regulate MT1-MMP and MMP2 expression through ERK2/SNAIL1 signaling in HCC. Additionally, collagen I can induce DDR2/ERK2/SNAIL1 signaling activation in HCC cells.
  
  
  CONCLUSIONS
  Our findings suggest that DDR2 plays an important role in promoting HCC cell invasion and migration, and may serve as a novel therapeutic target in HCC.
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China.
authors.forename: Binhui
authors.initials: B
authors.lastname: Xie
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
authors.forename: Weihao
authors.initials: W
authors.lastname: Lin
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China.
authors.forename: Junming
authors.initials: J
authors.lastname: Ye
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China.
authors.forename: Xiaonong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Medical Imaging, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester, LE1 9HN, UK.
authors.forename: Shiqiu
authors.initials: S
authors.lastname: Xiong
authors.affiliation: Department of Medical Imaging, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China. lihp1979@163.com.
authors.forename: Heping
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Medical Imaging, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China. tgs918@163.com.
authors.forename: Guosheng
authors.initials: G
authors.lastname: Tan
mesh_terms: D000328:Adult; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000401:mortality / Q000556:secondary; D002465:Cell Movement; D024042:Collagen Type I / Q000502:physiology; D000070818:Discoidin Domain Receptors; D018572:Disease-Free Survival; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D011379:Prognosis; D016016:Proportional Hazards Models; D055550:Protein Stability; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D024042:Collagen Type I; D011975:Receptors, Mitogen; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases