ABSTRACT
Osteosarcoma (OS) is an aggressive malignancy affecting mostly children and adolescents. MicroRNAs (miRNAs) play important roles in OS development and progression. Here we found that miR-16-1-3p and miR-16-2-3p "passenger" strands, as well as the "lead" miR-16-5p strand, are frequently downregulated and possess strong tumor suppressive functions in human OS. Furthermore, we report different although strongly overlapping functions for miR-16-1-3p and miR-16-2-3p in OS cells. Ectopic expression of these miRNAs affected primary tumor growth, metastasis seeding and chemoresistance and invasiveness of human OS cells. Loss-of-function experiments verified tumor suppressive functions of these miRNAs at endogenous levels of expression. Using RNA immunoprecipitation (RIP) assays, we identify direct targets of miR-16-1-3p and miR-16-2-3p in OS cells. Moreover, validation experiments identified FGFR2 as a direct target for miR-16-1-3p and miR-16-2-3p. Overall, our findings underscore the importance of passenger strand miRNAs, at least some, in osteosarcomagenesis.
Subject(s)
Down-Regulation , Lung Neoplasms/secondary , MicroRNAs/genetics , Osteonecrosis/pathology , Osteosarcoma/pathology , Receptor, Fibroblast Growth Factor, Type 2/genetics , Animals , Cell Line, Tumor , Cell Movement , Cell Proliferation , Drug Resistance, Neoplasm , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mice , Neoplasm Transplantation , Osteonecrosis/genetics , Osteosarcoma/geneticsABSTRACT
CD48 is a costimulatory receptor associated with human asthma. We aimed to assess the significance of the soluble form of CD48 (sCD48) in allergic and nonallergic asthma. Volunteer patients completed an asthma and allergy questionnaire, spirometry, methacholine challenge test, a common allergen skin prick test, and a complete blood count. sCD48, IgE, IL5, IL17A, IL33, and IFNγ were quantitated in serum by ELISA. Asthma was defined as positive methacholine challenge test or a 15% increase in FEV1 post bronchodilator in symptomatic individuals. Allergy was defined as positive skin test or IgE levels > 200 IU/l in symptomatic individuals. 137 individuals participated in the study: 82 (60%) were diagnosed with asthma of which 53 (64%) was allergic asthma. sCD48 levels were significantly elevated in patients with nonallergic asthma compared to control and to the allergic asthma cohort (median (IQR) pg/ml, 1487 (1338-1758) vs. 1308 (1070-1581), p < 0.01, and 1336 (1129-1591), p = 0.02, respectively). IL17A, IL33, and IFNγ levels were significantly elevated in allergic and nonallergic asthmatics when compared to control. No correlation was found between sCD48 level and other disease markers. sCD48 is elevated in nonallergic asthma. Additional studies are required for understanding the role of sCD48 in airway disease.
