Abstract
BackgroundThe abnormal proliferation and migration of airway smooth muscle (ASM) cells contributes to airway remodeling during asthma. MiR-19a has been demonstrated to promote cell proliferation and angiogenesis of several cancer types by regulating the PTEN/PI3K/AKT pathway. Our previous study has shown that High-mobility group box protein 1 (HMGB1) is involved in the pathogenesis of airway remodeling using a mouse model of chronic asthma. However, the effects of HMGB1 on proliferation and migration of ASM cells and its underlying mechanisms remain unknown.MethodsHuman ASM cells were obtained by primary explant techniques. MiR-19a expression was evaluated using qRT-PCR. Cell proliferation and migration were evaluated by the CCK-8 and the transwell migration assays, respectively. Transfection studies of ASM cells were performed to identify the underlying mechanisms.ResultsHMGB1 stimulated ASM cell proliferation and migration in a dose-dependent manner. The expression levels of miR-19a and the PTEN and AKT signaling proteins were also modulated by HMGB1. Functional studies indicated that overexpression of miR-19a enhanced the proliferation and migration of ASM cells, whereas inhibition of miR-19a decreased the proliferation and migration of ASM cells. Western blot analysis demonstrated that miR-19a negatively regulated PTEN expression and positively regulated p-AKT expression. MiR-19 only regulates the proliferation of HASM cells induced by HMGB1, but not PDGF, EGF, TGF-β1. Furthermore, we demonstrated that miR-19 contributed to the promoting effects of HMGB1 on ASM cells by targeting PTEN 3’-UTR.ConclusionOur results demonstrated that HMGB1 induced proliferation and migration of ASM cells via the miR-19a /PTEN/AKT axis and provided direct evidence on the role of HMGB1 in ASM cells proliferation in vitro. The present study further indicated that miR-19a may be explored as a potential novel therapeutic target to reverse proliferation and migration of ASM cells.
Highlights
High mobility group box-1 protein (HMGB1) is a chromosomal protein, which functions as a nuclear factor, and is considered an important mediator in tissue repair, inflammation, tumorigenesis and innate and adaptive immunities when it is present in the extracellular region [1]
Our results demonstrated that High-mobility group box protein 1 (HMGB1) induced proliferation and migration of airway smooth muscle (ASM) cells via the miR-19a /PTEN/AKT axis and provided direct evidence on the role of HMGB1 in ASM cells proliferation in vitro
We found that HMGB1 significantly induced proliferation of human airway smooth muscle (HASM) cells in a time- and dose-dependent manner compared with that of the vehicle control group (P
Summary
High mobility group box-1 protein (HMGB1) is a chromosomal protein, which functions as a nuclear factor, and is considered an important mediator in tissue repair, inflammation, tumorigenesis and innate and adaptive immunities when it is present in the extracellular region [1]. In a recent study we demonstrated that inhibition of HMGB1 activity decreased the levels of inflammatory mediators in the lung, whereas it could reverse airway remodeling in a allergen-induced murine model of chronic asthma [5]. We demonstrated that inhibition of HMGB1 activity decreased airway smooth muscle thickness in mice. The effects of HMGB1 on the function of ASM cells and the associated mechanism remain unknown. The abnormal proliferation and migration of airway smooth muscle (ASM) cells contributes to airway remodeling during asthma. Our previous study has shown that High-mobility group box protein 1 (HMGB1) is involved in the pathogenesis of airway remodeling using a mouse model of chronic asthma. The effects of HMGB1 on proliferation and migration of ASM cells and its underlying mechanisms remain unknown
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