期刊
ONCOTARGET
卷 7, 期 38, 页码 62070-62083出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.11386
关键词
tumor necrosis factor-alpha; ataxia-telangiectasia mutated; lung cancer; migration; matrix metalloproteinases
资金
- State Key Laboratory of Oncogenes and Related Genes [90-14-05]
- National Natural Science Foundation of China [81273203, 81201275]
- Natural Science Foundation of Fujian Province of China [2015J01353]
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-alpha) increasing tumor migration is still elusive. In the present study, we demonstrated that TNF-alpha 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-alpha activated ERK/p38-NF-kappa B pathway. The existence of TNF-alpha secreted in autocrine or paracrine manner by components of tumor microenvironment highlights the significance of TNF-alpha 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-alpha, 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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