title: The essential role of TNIK gene amplification in gastric cancer growth.
abstract: Traf2- and Nck-interacting kinase (TNIK) is one of the germinal center kinase family members involved in cytoskeleton organization and neuronal dendrite extension. Emerging evidence supports that TNIK is essential for activation of WNT signaling pathway in colon cancer growth. To search for novel genetic aberrations that drive carcinogenesis, we performed microarray-based comparative hybridization assay for gene copy number variations in primary tumor samples. Our data showed that TNIK gene was amplified in 7% (8/106) of Chinese gastric cancer patients. Theses amplifications were confirmed by fluorescence in situ hybridization analysis. PAMC82 human gastric cancer and T47D human breast cancer cell lines with TNIK amplification were identified to further understand the function of TNIK gene amplification. RNA-interference-mediated silencing of TNIK resulted in significant inhibition of cell growth and induction of cell death in TNIK-amplified, but not in TNIK-non-amplified, cell lines tested. This selective sensitivity to the TNIK inhibition was also observed under the effect of a small-molecule TNIK inhibitor. Furthermore, our data indicated that TNIK's role in gastric cancer growth was not dependent on Wnt signaling but rather was involved in AKT activation and cell autophagy. Together, our results suggest that TNIK is a novel therapeutic target in gastric cancer and TNIK amplification can be potentially used for patient selection.
authors.affiliation: Innovation Center China, AstraZeneca, Shanghai, China.
authors.forename: D-H
authors.initials: DH
authors.lastname: Yu
authors.affiliation: Innovation Center China, AstraZeneca, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 1] Innovation Center China, AstraZeneca, Shanghai, China [2] School of Life Science, Fudan University, Shanghai, China.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Surgery, Peking University Cancer Hospital and Institute, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.affiliation: Innovation Center China, AstraZeneca, Shanghai, China.
authors.forename: M
authors.initials: M
authors.lastname: Hu
authors.affiliation: Innovation Center China, AstraZeneca, Shanghai, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Innovation Center China, AstraZeneca, Shanghai, China.
authors.forename: G
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Innovation Center China, AstraZeneca, Shanghai, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Qian
authors.affiliation: Innovation Center China, AstraZeneca, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Fan
authors.affiliation: Innovation Center China, AstraZeneca, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Su
authors.affiliation: Innovation Center China, AstraZeneca, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Innovation Center China, AstraZeneca, Shanghai, China.
authors.forename: L
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Innovation Center China, AstraZeneca, Shanghai, China.
authors.forename: H
authors.initials: H
authors.lastname: Dong
authors.affiliation: Innovation Center China, AstraZeneca, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Yin
authors.affiliation: Innovation Center China, AstraZeneca, Shanghai, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Ji
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Surgery, Peking University Cancer Hospital and Institute, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Ji