Research Papers:

Ataxia-telangiectasia mutated activation mediates tumor necrosis factor-alpha induced MMP-13 up-regulation and metastasis in lung cancer cells

Hong Qiong Yan, Di Zhang, Yuan Yuan Shi, Xiang You, Lei Shi, Qing Li _ and Feng Guang Gao

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Oncotarget. 2016; 7:62070-62083. https://doi.org/10.18632/oncotarget.11386

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Hong Qiong Yan1, Di Zhang1,*, Yuan Yuan Shi1, Xiang You1, Lei Shi1, Qing Li1, Feng Guang Gao1,2

1Department of Immunology, Basic Medicine Science, Medical College, Xiamen University, Xiamen 361102, People’s Republic of China

2State Key Laboratory of Oncogenes and Related Genes, Shang Hai Jiao Tong University, Shanghai, 200032, People’s Republic of China

*Co-first author

Correspondence to:

Qing Li, email: [email protected]

Feng Guang Gao, email: [email protected]

Keywords: tumor necrosis factor-alpha, ataxia-telangiectasia mutated, lung cancer, migration, matrix metalloproteinases

Received: January 26, 2016     Accepted: August 08, 2016     Published: August 19, 2016


Despite that ataxia-telangiectasia mutated (ATM) is involved in IL-6 promoted lung cancer chemotherapeutic resistance and metastasis, the exact role of ATM in tumor necrosis factor-alpha (TNF-α) increasing tumor migration is still elusive. In the present study, we demonstrated that TNF-α promoted lung cancer cell migration by up-regulation of matrix metalloproteinase-13 (MMP-13). Notably, by gene silencing or kinase inhibition, we proposed for the first time that ATM is a key up-stream regulator of TNF-α activated ERK/p38-NF-κB pathway. The existence of TNF-α secreted in autocrine or paracrine manner by components of tumor microenvironment highlights the significance of TNF-α in inflammation-associated tumor metastasis. Importantly, in vivo lung cancer metastasis test showed that ATM depletion actually reduce the number of metastatic nodules and cancer nests in lung tissues, verifying the critical role of ATM in metastasis. In conclusion, our findings demonstrate that ATM, which could be activated by lung cancer-associated TNF-α, up-regulate MMP-13 expression and thereby augment tumor metastasis. Therefore, ATM might be a promising target for prevention of inflammation-associated lung cancer metastasis.

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