title: KIF5B-RET fusion kinase promotes cell growth by multilevel activation of STAT3 in lung cancer.
abstract: BACKGROUND
  Lung cancer in nonsmokers tends to be driven by a single somatic mutation or a gene fusion. KIF5B-RET fusion is an oncogene identified in non-small cell lung cancers. In this study, we verified the oncogenic activity of KIF5B-RET fusion and investigated how KIF5B-RET activates the specific signaling pathways for cellular transformation. We aimed to provide a basis for the further development of the therapy for KIF5B-RET positive lung cancer patients.
  
  
  METHODS
  RT-PCR was used to screen for KIF5B-RET fusions in Chinese lung cancer patients. To verify the oncogenic activity of KIF5B-RET kinase in lung cancer cells, we manipulated its expression genetically followed by colony formation and tumor formation assays. The mechanism by which KIF5B-RET kinase induces proliferation was investigated by western blot, coimmunoprecipitation, and administration of RET, MAPK and STAT3 inhibitors.
  
  
  RESULTS
  Our study identified a KIF5B-RET fusion in Chinese NSCLC patients and demonstrated that KIF5B-RET transfected cells showed a significantly increased proliferation rate and colony-forming ability. Furthermore, we found that KIF5B-RET fusion kinase induced multilevel activation of STAT3 at both Tyr705 and Ser727, and KIF5B-RET-STAT3 signaling related inhibitors repressed the proliferation and tumorigenicity of lung cancer cells significantly.
  
  
  CONCLUSIONS
  Our data suggest that KIF5B-RET promotes the cell growth and tumorigenicity of non-small cell lung cancers through multilevel activation of STAT3 signaling, providing possible strategies for the treatment of KIF5B-RET positive lung cancers.
authors.forename: YingYing
authors.initials: Y
authors.lastname: Qian
authors.forename: Shoujie
authors.initials: S
authors.lastname: Chai
authors.forename: Zuyu
authors.initials: Z
authors.lastname: Liang
authors.forename: Yongfang
authors.initials: Y
authors.lastname: Wang
authors.forename: You
authors.initials: Y
authors.lastname: Zhou
authors.forename: Xia
authors.initials: X
authors.lastname: Xu
authors.forename: Chenchen
authors.initials: C
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Jingxing
authors.initials: J
authors.lastname: Si
authors.forename: Feiteng
authors.initials: F
authors.lastname: Huang
authors.forename: Zhangdan
authors.initials: Z
authors.lastname: Huang
authors.forename: Wei
authors.initials: W
authors.lastname: Hong
authors.affiliation: Department of Respiratory Medicine, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China. kaiw@zju.edu.cn.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D006801:Humans; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000096:biosynthesis / Q000235:genetics*; D014178:Translocation, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: C573239:KIF5B-RET fusion protein, human; D015514:Oncogene Proteins, Fusion; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051096:Proto-Oncogene Proteins c-ret