ABSTRACT
Aberrant expression of the pluripotency factor OCT4A in embryonal tumors of the central nervous system (CNS) is a key factor that contributes to tumor aggressiveness and correlates with poor patient survival. OCT4A overexpression has been shown to up-regulate miR-367, a microRNA (miRNA) that regulates pluripotency in embryonic stem cells and stem-like aggressive traits in cancer cells. Here, we show that (a) miR-367 is carried in microvesicles derived from embryonal CNS tumor cells expressing OCT4A; and (b) inhibition of miR-367 in these cells attenuates their aggressive traits. miR-367 silencing in OCT4A-overexpressing tumor cells significantly reduced their proliferative and invasive behavior, clonogenic activity, and tumorsphere generation capability. In vivo, targeting of miR-367 through direct injections of a specific inhibitor into the cerebrospinal fluid of Balb/C nude mice bearing OCT4A-overexpressing tumor xenografts inhibited tumor development and improved overall survival. miR-367 was also shown to target SUZ12, one of the core components of the polycomb repressive complex 2 known to be involved in epigenetic silencing of pluripotency-related genes, including POU5F1, which encodes OCT4A. Our findings reveal possible clinical applications of a cancer stemness pathway, highlighting miR-367 as a putative liquid biopsy biomarker that could be further explored to improve early diagnosis and prognosis prediction, and potentially serve as a therapeutic target in aggressive embryonal CNS tumors.
Subject(s)
Biomarkers, Tumor , Central Nervous System Neoplasms , Gene Silencing , MicroRNAs , Neoplasms, Germ Cell and Embryonal , Neoplastic Stem Cells , RNA, Neoplasm , Animals , Biomarkers, Tumor/antagonists & inhibitors , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cell Line, Tumor , Central Nervous System Neoplasms/drug therapy , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/metabolism , Central Nervous System Neoplasms/pathology , HEK293 Cells , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , MicroRNAs/antagonists & inhibitors , MicroRNAs/genetics , MicroRNAs/metabolism , Neoplasms, Germ Cell and Embryonal/drug therapy , Neoplasms, Germ Cell and Embryonal/genetics , Neoplasms, Germ Cell and Embryonal/metabolism , Neoplasms, Germ Cell and Embryonal/pathology , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , RNA, Neoplasm/antagonists & inhibitors , RNA, Neoplasm/genetics , RNA, Neoplasm/metabolism , Xenograft Model Antitumor AssaysABSTRACT
To explore the hypothesis that air pollution promotes cardiovascular changes, Swiss mice were continuously exposed, since birth, in two open-top chambers (filtered and nonfiltered for airborne particles Subject(s)
Aging/physiology
, Air Pollutants/adverse effects
, Air Pollution/adverse effects
, Cities
, Coronary Vessels/pathology
, Inhalation Exposure/adverse effects
, Particulate Matter/adverse effects
, Animals
, Brazil
, Collagen/analysis
, Elastic Tissue/pathology
, Fibrosis/pathology
, Male
, Mice
, Mice, Inbred Strains
, Particle Size
, Time Factors
, Toxicity Tests, Chronic
, Tunica Intima/pathology
, Tunica Media/pathology
ABSTRACT
RATIONALE: Chronic exposure to air pollution has been associated with adverse effects on children's lung growth. OBJECTIVES: We analyzed the effects of chronic exposure to urban levels of particulate matter (PM) on selected phases of mouse lung development. METHODS: The exposure occurred in two open-top chambers (filtered and nonfiltered) placed 20 m from a street with heavy traffic in São Paulo, 24 hours/day for 8 months. There was a significant reduction of the levels of PM(2.5) inside the filtered chamber (filtered = 2.9 +/- 3.0 microg/m(3), nonfiltered = 16.8 +/- 8.3 microg/m(3); P = 0.001). At this exposure site, vehicular sources are the major components of PM(2.5) (PM Subject(s)
Air Pollutants/adverse effects
, Inhalation Exposure/adverse effects
, Particulate Matter/adverse effects
, Pulmonary Alveoli
, Animals
, Brazil
, Disease Models, Animal
, Female
, Male
, Mice
, Pulmonary Alveoli/growth & development
, Pulmonary Alveoli/pathology
, Respiratory Function Tests
, Urban Population
, Vehicle Emissions