Defects in the Fanconi Anemia Pathway in Head and Neck Cancer Cells Stimulate Tumor Cell Invasion through DNA-PK and Rac1 Signaling.
Defects in the Fanconi Anemia Pathway in Head and Neck Cancer Cells Stimulate Tumor Cell Invasion through DNA-PK and Rac1 Signaling.
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DOI：
10.1158/1078-0432.ccr-15-2209
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发表时间：
2016-04-15
期刊：
影响因子：
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通讯作者：
Wells SI
中科院分区：
文献类型：
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作者：
Romick-Rosendale LE;Hoskins EE;Privette Vinnedge LM;Foglesong GD;Brusadelli MG;Potter SS;Komurov K;Brugmann SA;Lambert PF;Kimple RJ;Virts EL;Hanenberg H;Gillison ML;Wells SI
Head and neck squamous cell carcinoma (HNSCC) remains a devastating disease, and FA gene mutations and transcriptional repression are common. Invasive tumor behaviour is associated with poor outcome, but relevant pathways triggering invasion are poorly understood. There is a significant need to improve our understanding of genetic pathways and molecular mechanisms driving advanced tumor phenotypes, in order to develop tailored therapies. Here we sought to investigate the phenotypic and molecular consequences of FA pathway loss in HNSCC cells. Using sporadic HNSCC cell lines with and without FA gene knockdown, we sought to characterize the phenotypic and molecular consequences of FA deficiency. FA pathway inactivation was confirmed by the detection of classical hallmarks of FA following exposure to DNA crosslinkers. Cells were subjected to RNA sequencing with qRT-PCR validation, followed by cellular adhesion and invasion assays in the presence and absence of DNA-PK and Rac1 inhibitors. We demonstrate that FA loss in HNSCC cells leads to cytoskeletal reorganization and invasive tumor cell behavior in the absence of proliferative gains. We further demonstrate that cellular invasion following FA loss is mediated, at least in part, through NHEJ-associated DNA-dependent protein kinase (DNA-PK) and downstream Rac1 GTPase activity. These findings demonstrate that FA loss stimulates HNSCC cell motility and invasion, and implicate a targetable DNA-PK/Rac1 signaling axis in advanced tumor phenotypes.
