title: Identification of novel driver mutations of the discoidin domain receptor 2 (DDR2) gene in squamous cell lung cancer of Chinese patients.
abstract: BACKGROUND
  Although many of the recently approved genomically targeted therapies have improved outcomes for patients in non-small-cell lung cancer (NSCLC) with lung adenocarcinoma, little is known about the genomic alterations that drive lung squamous cell cancer (SCC) and development of effective targeted therapies in lung SCC is a promising area to be further investigated. Discoidin domain receptor 2 (DDR2), is a novel receptor tyrosine kinases that respond to several collagens and involved in tissue repair, primary and metastatic cancer progression.
  
  
  METHODS
  Expression of DDR2 mRNA was analyzed in 54 lung SCC tissues by qRT-PCR. Over-expression approaches were used to investigate the biological functions of DDR2 and its' mutations in lung SCC cells. Conventional Sanger sequencing was used to investigate the mutations of DDR2 gene in 86 samples. The effect of DDR2 and its' mutations on proliferation was evaluated by MTT and colony formation assays; cell migration and invasion was evaluated by trasnwell assays. Lung SCC cells stably transfected with pEGFP-DDR2 WT, pEGFP-DDR2-S131C or empty vector were injection into nude mice to study the effect of DDR2 and its' mutation on tumorigenesis in vivo. Protein and mRNA expression levels of E-cadherin and MMP2 were determined by qRT-PCR and western blot analysis. Differences between groups were tested for significance using Student's t-test (two-tailed).
  
  
  RESULTS
  In this study, we found that DDR2 mRNA levels were significantly decreased in 54 lung SCC tissues compared with normal lung tissues. Moreover, there were 3 novel DDR2 mutations (G531V, S131C, T681I) in 4 patients and provide the mutation rate of 4.6% in the 86 patients with lung SCC. The mutation of S131C in DDR2 could promote lung SCC cells proliferation, migration and invasion via inducing MMP-2, but reducing E-cadherin expression.
  
  
  CONCLUSIONS
  These data indicated that the novel DDR2 mutation may contribute to the development and progression of lung SCC and this effect may be associated with increased proliferation and invasiveness, at least in part, via regulating E-cadherin expression.
authors.forename: Liyun
authors.initials: L
authors.lastname: Miao
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Wang
authors.forename: Suhua
authors.initials: S
authors.lastname: Zhu
authors.forename: Minke
authors.initials: M
authors.lastname: Shi
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Jingjing
authors.initials: J
authors.lastname: Ding
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Qing
authors.initials: Q
authors.lastname: Ye
authors.forename: Hourong
authors.initials: H
authors.lastname: Cai
authors.forename: Deping
authors.initials: D
authors.lastname: Zhang
authors.forename: Hongbing
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Respiratory Medicine, Jinling Hospital, Medical School of Nanjing University, East Zhongshan Road 305#, Nanjing 210002, Jiangsu Province China. yong_song6310@yahoo.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Song
mesh_terms: D000818:Animals; D015820:Cadherins / Q000096:biosynthesis; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002681:China; D000070818:Discoidin Domain Receptors; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics*; D011975:Receptors, Mitogen / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D015820:Cadherins; D011975:Receptors, Mitogen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases