RESUMO
Expression of Frizzled 9 (FZD9) is critical to the activity of the lung cancer chemoprevention agent and prostacyclin analogue, iloprost. FZD9 is required in lung epithelial cells for iloprost to activate peroxisome proliferator activated receptor gamma (PPARG) and related anti-tumor signaling. We aimed to investigate which miRNA regulate FZD9 in the context of cigarette smoke exposure and iloprost treatment. We found that miR-520a-5p binds the FZD9 3'UTR in lung cell lines and alters activity and expression of FZD9 downstream targets. Cigarette smoke condensate (CSC) increases expression of miR-520a-5p, while iloprost decreases expression. Cancer promoting effects of a miR-520a-5p mimic were rescued with iloprost treatment, and effects of cigarette smoke were partially rescued with a miR-520a-5p inhibitor. Here we confirm miR-520a-5p as a regulator of FZD9 activity and a mediator of CSC and iloprost effects in the lung. Targeting miR-520a-5p could be an approach to restoring FZD9 expression and improving response to iloprost lung cancer chemoprevention.
Assuntos
Fumar Cigarros/efeitos adversos , Receptores Frizzled/genética , Iloprosta/farmacologia , Neoplasias Pulmonares/genética , MicroRNAs/genética , Linhagem Celular Tumoral , Quimioprevenção , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Receptores Frizzled/química , Receptores Frizzled/metabolismo , Humanos , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/prevenção & controle , MicroRNAs/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Ligação Proteica , Domínios ProteicosRESUMO
Frizzled (FZD) transmembrane receptors are well known for their role in ß-catenin signaling and development and now understanding of their role in the context of cancer is growing. FZDs are often associated with the process of epithelial to mesenchymal transition (EMT) through ß-catenin, but some also influence EMT through non-canonical pathways. With ten different FZDs, there is a wide range of activity from oncogenic to tumor suppressive depending on the tissue context. Alterations in FZD signaling can occur during development of premalignant lesions, supporting their potential as targets of chemoprevention agents. Agonizing or antagonizing FZD activity may affect EMT, which is a key process in lesion progression often targeted by chemoprevention agents. Recent studies identified a specific FZD as important for activity of an EMT inhibiting chemopreventive agent and other studies have highlighted the previously unrecognized potential for targeting small molecules to FZD receptors. This work demonstrates the value of investigating FZDs in chemoprevention and here we provide a review of FZDs in cancer EMT and their potential as chemoprevention targets.
