RESUMEN
Osteosarcoma (OS) is a lethal bone malignancy. Circular RNAs (circRNAs) have emerged as important regulators of OS development. CircRNA cyclin dependent kinase 14 (circ_CDK14) was reported to be a potential oncogene in OS. However, the mechanistic pathway by which circ_CDK14 functions in OS is largely unknown. The relative expression of circ_CDK14, microRNA (miR)-520a-3p, and GRB2 Associated Binding Protein 1 (GAB1) was evaluated by quantitative real-time PCR and western blot assays. Flow cytometry was employed to monitor cell cycle distribution and apoptosis. Methyl thiazolyl tetrazolium (MTT) and colony formation assays were performed to assess cell viability and colony formation ability, respectively. Western blot assay was also used to detect the expression of apoptosis-related proteins. Transwell assay was carried out to monitor cell migration and invasion. Additionally, the target association between miR-520a-3p and circ_CDK14 or GAB1 was confirmed by a dual-luciferase reporter assay. Xenograft assay was applied to investigate the role of circ_CDK14 in vivo. Circ_CDK14 and GAB1 expression was upregulated, while miR-520a-3p was downregulated in OS tissues and cells. Circ_CDK14 depletion hindered OS cell proliferation, metastasis, and tumorigenesis while facilitated apoptosis, which were all ameliorated by miR-520a-3p inhibition. Circ_CDK14 could sponge miR-520a-3p. miR-520a-3p targeted GAB1 to repress OS cell proliferation and metastasis. Circ_CDK14 knockdown blocked OS tumor growth in vivo. Circ_CDK14 might positively affect OS development by modulating the miR-520a-3p/GAB1 axis.
Asunto(s)
MicroARNs , Osteosarcoma , Proteínas Adaptadoras Transductoras de Señales/genética , Línea Celular Tumoral , Quinasas Ciclina-Dependientes , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , Osteosarcoma/genética , ARN CircularRESUMEN
Extensive solar ultraviolet B (UVB) exposure of the skin results in inflammation and oxidative stress, which may contribute to skin cancer. Natural products have attracted attention for their role in the effective treatment of cutaneous neoplasia. Juglanin is purified from the crude extract of Polygonum aviculare, exhibiting antioxidant, antiinflammatory and anticancer activities. Jugalanin was used in the current study to investigate whether it may ameliorate UVB irradiationinduced skin damage by reducing oxidative stress and suppressing the inflammatory response in vivo and in vitro. In the present study, hairless mice were exposed to UVB irradiation in the absence or presence of juglanin administration for 10 weeks. The findings indicated that juglanin inhibited UVBinduced hyperplasia and decreased infiltration in the skin of mice. UVB exposureinduced oxidative stress in mice and cells was inhibited by juglanin via enhancing antioxidant activity. Additionally, juglanin markedly reduced proinflammatory cytokine release, including cyclic oxidase 2, interleukin1ß and tumor necrosis factorα, triggered by chronic UVB irradiation. Juglaninameliorated skin damage was associated with its suppression of mitogen activated protein kinases (MAPKs), including p38, extracellular signal regulated 1/2, and cJun Nterminal kinases, as well as nuclear factor (NF)κB signaling pathways, which was dependent on nuclear factorE2related factor 2 (Nrf2)modulated reactive oxygen species generation. Taken together, these data indicate that juglanin protected against UVBtriggered oxidative stress and inflammatory responses by suppressing MAPK and NFκB activation via enhancing Nrf2 activity.
Asunto(s)
Glicósidos/farmacología , Quempferoles/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Piel/efectos de los fármacos , Piel/metabolismo , Rayos Ultravioleta/efectos adversos , Animales , Western Blotting , Línea Celular , Supervivencia Celular/efectos de los fármacos , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunohistoquímica , Ratones , Factor 2 Relacionado con NF-E2/genética , Estrés Oxidativo/efectos de los fármacos , Peroxidasa/genética , Peroxidasa/metabolismo , Transducción de Señal , Piel/efectos de la radiación , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Solar ultraviolet B (UVB) radiation is known to trigger inflammation, oxidative stress and apoptotic responses through various signaling pathways, which eventually lead to skin cancer. The present study investigated whether liquiritin suppresses UVBinduced skin injury in vivo and in vitro using SKH1 hairless mice and HACAT cells, respectively. The animals were exposed to UVB irradiation (180 mJ/cm2) for 20 min, followed by liquiritin treatment. The findings indicated that UVB exposure resulted in the excessive release of proinflammatory cytokines, including interleukin (IL)1ß, tumor necrosis factor (TNF)α, IL18, IL6 and cyclooxygenase (COX)2, which were dependent on the tolllike receptor (TLR)4/myeloid differentiation factor 88 (MyD88)/nuclear factorκB (NFκB) signaling pathway. Oxidative stress was also observed, evidenced by reduced antioxidants and elevated oxidants. Apoptosis, examined using terminal deoxynucleotidyl transferase dUTP nick end labeling and crystal violet staining, suggested that UVB irradiation caused cell death in vivo and in vitro, which was closely associated with p38/cJun Nterminal kinase and caspase activity. Of note, liquiritin treatment in mice and cells exposed to UVB showed reduced inflammatory response, oxidative stress and apoptosis through inhibiting the activation of TLR4/MyD88/NFκB mitogenactivated protein kinases and caspase pathways, and downregulating the release of oxidants. Overall, the data revealed that liquiritin may be a useful compound against UVBinduced skin injury.
Asunto(s)
Apoptosis , Flavanonas/uso terapéutico , Glucósidos/uso terapéutico , Inflamación/tratamiento farmacológico , Transducción de Señal , Piel/efectos de la radiación , Rayos Ultravioleta , Animales , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Caspasas/metabolismo , Muerte Celular/efectos de los fármacos , Muerte Celular/efectos de la radiación , Línea Celular , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Citocinas/metabolismo , Femenino , Flavanonas/farmacología , Glucósidos/farmacología , Humanos , Inflamación/patología , Inflamación/prevención & control , Mediadores de Inflamación/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , FN-kappa B/metabolismo , Oxidantes/metabolismo , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/efectos de la radiación , Transducción de Señal/efectos de los fármacos , Transducción de Señal/efectos de la radiación , Piel/efectos de los fármacos , Piel/patología , Receptor Toll-Like 4/metabolismoRESUMEN
Salidroside (SR) is a main component of Rhodiola rosea L. and exhibits a variety of pharmacologic properties. The present study was carried out to explore the potential effect of SR against skin cancer induced by 7,12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13acetate (TPA) in female Institute for Cancer Research (ICR) mice and to reveal the underlying molecular targets regulated by SR. The mice were randomly divided into 4 groups: control, DMBA/TPA, DMBA/TPA+SR (20 mg/kg) and DMBA/TPA+SR (40 mg/kg). SR was administered to mice five times a week after DMBA treatments. In our study, we found that SR dose-dependently ameliorated skin cancer incidence and the multiplicity in the animal models by reducing the release of inflammation-related cytokines, including tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß), interleukin-18 (IL-18), interleukin-6 (IL-6), cyclooxygenase 2 (COX2) and transforming growth factor ß-1 (TGF-ß1). Suppression of the nuclear factor (NF)-κB signaling pathway by SR was effective to prevent skin carcinogenesis. Furthermore, TUNEL analysis indicated that compared to the DMBA/TPA group, enhanced apoptosis was observed in the DMBA/TPA+SR group. In addition, p53 expression levels were increased by SR in the DMBA/TPA-induced mice. Therefore, SR was effective for inducing apoptosis during skin cancer progression triggered by DMBA/TPA. Consistently, p21, p53 upregulated modulator of apoptosis (PUMA), Bax and caspase-3 were highly induced by SR to enhance the apoptotic response for preventing skin cancer. Moreover, in vitro, we found that SR dramatically reduced the inflammatory response, while enhancing the aoptotic response by blocking NF-κB and activating caspase-3 pathways, respectively. In addition, flow cytometric analysis further confirmed the induction of apoptosis by SR in DMBA-treated cells in vitro. Taken together, the in vivo and in vitro studies illustrated that SR might be a promising compound to reduce skin cancer risk.