title: IL-6, IL-8, MMP-2, MMP-9 are overexpressed in Fanconi anemia cells through a NF-κB/TNF-α dependent mechanism.
abstract: Fanconi anemia (FA) is a rare autosomal recessive genetic disorder associated with a bone-marrow failure, genome instability, hypersensitivity to DNA crosslinking agents and a predisposition to cancer. Mutations have been documented in 16 FA genes that participate in the FA-BRCA DNA repair pathway, a fundamental pathway in the development of the disease and the presentation of its symptoms. FA cells have been characterized by an overproduction of cytokines, MAPKs, and Interleukins. Through this study we have identified the overexpression of additional secretory factors such as IL-6, IL-8, MMP-2, and MMP-9 in FA cells and in cells depleted of FANCA or FANCC and proved that their expression is under the control of NF-κB/TNF-α signaling pathways. We also demonstrated that these overexpressed secretory factors were effective in promoting the proliferation, migration, and invasion of surrounding tumor cells a fundamental event in the process of epithelial mesenchymal transition (EMT) and that they also modulated the expression of EMT markers such as E-cadherin and SNAIL. Overall our data suggest that the upregulation of EMT promoting factors in FA may contribute to predisposing FA patients to cancer, thereby providing new insights into possible therapeutic interventions.
authors.affiliation: Institute of Genetics and Molecular and Cellular Biology, Department of Functional Genomics and Cancer Biology, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale Illkirch Cedex, France.
authors.forename: Alexey
authors.initials: A
authors.lastname: Epanchintsev
authors.affiliation: Department of Biotechnology, Stem Cell and Molecular Biology Laboratory, Indian Institute of Technology Madras, Chennai, India.
authors.forename: Pavithra
authors.initials: P
authors.lastname: Shyamsunder
authors.affiliation: Department of Biotechnology, Stem Cell and Molecular Biology Laboratory, Indian Institute of Technology Madras, Chennai, India.
authors.forename: Rama S
authors.initials: RS
authors.lastname: Verma
authors.affiliation: Novosibirsk Institute of Molecular Biology and Biophysics, Novosibirsk, Russia.|Cancer & Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore, Singapore.|Queen's University Belfast, Belfast, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Lyakhovich
mesh_terms: D015820:Cadherins / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005199:Fanconi Anemia / Q000235:genetics*; D052217:Fanconi Anemia Complementation Group A Protein / Q000235:genetics; D052218:Fanconi Anemia Complementation Group C Protein / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D016209:Interleukin-8 / Q000235:genetics*; D061986:MCF-7 Cells; D020778:Matrix Metalloproteinase 2 / Q000235:genetics*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D015820:Cadherins; C498471:FANCA protein, human; C497651:FANCC protein, human; D052217:Fanconi Anemia Complementation Group A Protein; D052218:Fanconi Anemia Complementation Group C Protein; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D000071250:Snail Family Transcription Factors; C439524:TNF protein, human; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: EMT; Fanconi anemia; cancer micro-environment; interleukins; metalloproteinases