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.

journal_name

Mol Cancer

journal_title

Molecular cancer

authors

Qian Y,Chai S,Liang Z,Wang Y,Zhou Y,Xu X,Zhang C,Zhang M,Si J,Huang F,Huang Z,Hong W,Wang K

doi

10.1186/1476-4598-13-176

subject

Has Abstract

pub_date

2014-07-21 00:00:00

pages

176

issn

1476-4598

pii

1476-4598-13-176

journal_volume

13

pub_type

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