title: Ataxia-telangiectasia mutated activation mediates tumor necrosis factor-alpha induced MMP-13 up-regulation and metastasis in lung cancer cells.
abstract: 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.
authors.affiliation: Department of Immunology, Basic Medicine Science, Medical College, Xiamen University, Xiamen 361102, People's Republic of China.
authors.forename: Hong Qiong
authors.initials: HQ
authors.lastname: Yan
authors.affiliation: Department of Immunology, Basic Medicine Science, Medical College, Xiamen University, Xiamen 361102, People's Republic of China.
authors.forename: Di
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Basic Medicine Science, Medical College, Xiamen University, Xiamen 361102, People's Republic of China.
authors.forename: Yuan Yuan
authors.initials: YY
authors.lastname: Shi
authors.affiliation: Department of Immunology, Basic Medicine Science, Medical College, Xiamen University, Xiamen 361102, People's Republic of China.
authors.forename: Xiang
authors.initials: X
authors.lastname: You
authors.affiliation: Department of Immunology, Basic Medicine Science, Medical College, Xiamen University, Xiamen 361102, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.affiliation: Department of Immunology, Basic Medicine Science, Medical College, Xiamen University, Xiamen 361102, People's Republic of China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Immunology, Basic Medicine Science, Medical College, Xiamen University, Xiamen 361102, People's Republic of China.|State Key Laboratory of Oncogenes and Related Genes, Shang Hai Jiao Tong University, Shanghai, 200032, People's Republic of China.
authors.forename: Feng Guang
authors.initials: FG
authors.lastname: Gao
mesh_terms: D000072283:A549 Cells; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007249:Inflammation; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008175:Lung Neoplasms / Q000378:metabolism*; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D009362:Neoplasm Metastasis; D034741:RNA, Small Interfering / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D016328:NF-kappa B; D034741:RNA, Small Interfering; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13
keywords: ataxia-telangiectasia mutated; lung cancer; matrix metalloproteinases; migration; tumor necrosis factor-alpha