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.

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“…For example, TNIK forms a complex with β-catenin and TCF-4 in colorectal cancer, only activating TCF-4 at the S154 residue, and then the phosphorylated TCF-4 recruits to the promoters of Wnt target genes. By contrast, Yu DH et al [8] demonstrated an oncogenic role of TNIK in gastric cancer independent of Wnt/β-catenin pathway. ShRNA-mediated TNIK silencing did not result in decreased expression of genes controlled by Wnt/β-catenin pathway, but in reduction of p-Akt and induction of LC3, suggesting the tumorigenic behavior of TNIK in gastric cancer in a manner of PI3K/Akt pathway.…”

“…SiRNA-mediated knockdown of TNIK inhibits tumor cell growth and migration and promotes apoptosis and autophagy in several tumor cell lines [7,8]. These studies revealed a crucial role of TNIK in the initiation and progression of gastric and colorectal cancer.…”

“…The growth inhibition could be reversed by restoration of the catalytic domain of TNIK, unraveling the necessity of its enzymatic activity in colorectal carcinogenesis and progression [7]. Similarly, Yu DH et al [8] also found TNIK amplified in gastric cancer by screening gene copy number variations. Surprisingly, it did not facilitate tumorigenesis through Wnt/β-catenin but through PI3K/Akt pathway.…”

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