title: T cell factor-4 functions as a co-activator to promote NF-κB-dependent MMP-15 expression in lung carcinoma cells.
abstract: Both TCF-4 and MMP-15 are closely linked to the development of lung cancer, while the regulatory role of TCF-4 in MMP-15 expression is still obscure. Here we found that expression of TCF-4 and MMP-15 was increased in lung cancer cells or tissues versus the normal ones. With gain-or loss-of -function studies, we demonstrated that TCF-4 positively regulated MMP-15 expression in mRNA and protein levels. With reporter gene assay, we found that TCF-4 regulated MMP-15 expression via a potential NF-κB binding element locating at -2833/-2824 in the mouse MMP-15 promoter. With ChIP and immunoblotting assays, we identified that TCF-4 functioned as a co-activator to potentiate the binding between p65 and MMP-15 promoter. Functionally, TCF-4 silence attenuated the migration activity of LLC cells, while additional overexpression of MMP-15 rescued this effect in cell scratch test and transwell migration assay. In xenograft model, TCF-4 silence-improved tumor lesions in lungs and survival time of LLC-tumor bearing mice were abolished by MMP-15 overexpression. In conclusion, we are the first to identify TCF-4 as a co-activator of NF-κB p65 to promote MMP-15 transcription and potentiate the migration activity of the lung cancer cells. Our findings shed light on the therapeutic strategies of this malignancy.
authors.affiliation: Department of Respiratory Medicine, First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China.
authors.forename: Yuliang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Respiratory Medicine, Xinqiao Hospital, Third Military Medical University, 400037, Chongqing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Respiratory Medicine, First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China.
authors.forename: Shuliang
authors.initials: S
authors.lastname: Guo
authors.affiliation: Department of Respiratory Medicine, First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
mesh_terms: D000483:Alleles; D000818:Animals; D002277:Carcinoma / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D017930:Genes, Reporter; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D053517:Matrix Metalloproteinase 15 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D058118:Transcription Factor 7-Like 2 Protein / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C507098:MMP15 protein, human; C507100:Mmp15 protein, mouse; C498143:RELA protein, human; C498144:Rela protein, mouse; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D051996:Transcription Factor RelA; D004247:DNA; D053517:Matrix Metalloproteinase 15