ABSTRACT
Previously we have reported that metastatic melanoma cell lines and tumor specimens have reduced expression of ADAR1 and consequently are impaired in their ability to perform A-to-I microRNA (miRNA) editing. The effects of A-to-I miRNAs editing on melanoma growth and metastasis are yet to be determined. Here we report that miR-378a-3p is undergoing A-to-I editing only in the non-metastatic but not in metastatic melanoma cells. The function of the edited form is different from its wild-type counterpart. The edited form of miR-378a-3p preferentially binds to the 3'-UTR of the PARVA oncogene and inhibits its expression, thus preventing the progression of melanoma towards the malignant phenotype. Indeed, edited miR-378a-3p but not its WT form inhibits melanoma metastasis in vivo. These results further emphasize the role of RNA editing in melanoma progression.
Subject(s)
Adenosine/genetics , Gene Expression Regulation, Neoplastic , Inosine/genetics , Melanoma/pathology , MicroRNAs/genetics , Microfilament Proteins/genetics , RNA Editing , Skin Neoplasms/pathology , 3' Untranslated Regions , Animals , Cell Line, Tumor , Cell Proliferation , Disease Progression , Epigenesis, Genetic , Female , Humans , Melanoma/genetics , Mice , Mice, Nude , Neoplasm Invasiveness , Neoplasm Metastasis , Oncogenes , Skin Neoplasms/geneticsABSTRACT
BACKGROUND: Intramural delivery of lipids into the coronaries of pigs fed high-cholesterol diet results in the formation of localized atherosclerotic-like lesions within 12 weeks. These lesions are located in positively remodeled vessels and are associated to the development of abundant adventitial vasa vasorum and mononuclear cell infiltrate. In this study, we aimed to analyze the degree of expression of various inflammatory chemokines within the developed lesions compared with control segments injected with saline. METHODS: Balloon injury was performed in 15 coronary arteries of pigs fed high-cholesterol diet for 12 weeks. Two weeks after procedure, 60 coronary segments were randomized to either intramural injections of complex lipids (n=30) or normal saline (n=30). Neovessel density in the lesions was analyzed by lectin stain. Segments were processed for RNA expression of inflammatory chemokines such as monocyte chemoattractant protein-1 and vascular endothelial growth factor. RESULTS: At 12 weeks, the percentage area of stenosis seen in histological sections was modest in both groups (lipids: 17.3±15 vs. saline: 32.4±22.8, P=.017). The lipid group showed higher vasa vasorum (VV) quantity (saline: 18.2±14.9 VV/section vs. lipids: 30.6±21.6 VV/section, P<.05) and vasa vasorum density (saline: 7.3±4.6 VV/mm(2) vs. lipids: 16.5±9 VV/mm(2), P<.001). In addition, monocyte chemoattractant protein-1 expression was higher in the lipid group (1.5±1.12) compared with saline control group (0.83±0.34, P<.01). Vascular endothelial growth factor expression was also higher in the lipid group (1.36±0.9) compared with saline group (0.87±0.33, P<.05). CONCLUSION: The intramural injection of complex lipids into the coronary arteries of pigs maintained in a high-cholesterol diet results in focal lesions located in positively remodeled vessels that have a high neovessel count and express proinflammatory chemokines.
