RESUMO
Clear cell renal cell carcinoma (ccRCC) is one of the most common types of malignant tumors and early detection contributes to a better prognosis. Finding new biomarkers for the diagnosis or treatment remains meaningful. DEF6 guanine nucleotide exchange factor (DEF6) is upregulated in ccRCC compared to normal controls, but the relationship between DEF6 expression and prognosis in ccRCC is unclear. Moreover, the potential biological functions of DEF6 in ccRCC remains unclear. In the present study, the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), TISIDB and the clinical database of the Peking University First Hospital were used to analyze DEF6 expression in ccRCC. Immunohistochemistry (IHC), western blotting and reverse transcriptionquantitative PCR were used to examine the DEF6 protein and mRNA expression levels in cell lines and clinical samples. Subsequently, the KaplanMeier method and Cox regression analyses were used to determine the impact of DEF6 expression on the overall survival of patients alongside other clinical variables in both the TCGA database and the present clinical database. The results showed that both DEF6 mRNA and protein expression levels were upregulated in ccRCC compared to normal controls. The KaplanMeier survival analysis showed that patients with high DEF6 expression had poor prognoses from both the TCGA database and the present clinical database. Univariate survival analysis and multivariate survival analysis revealed that DEF6 could be an independent prognostic factor for ccRCC. Additionally, bioinformatics analysis indicated that differentially expressed genes related to DEF6 expression influenced ccRCC by regulating the tumor immune microenvironment. In conclusion, overexpression of DEF6 is significantly correlated with a poor prognosis for patients with ccRCC and DEF6 may influence the biological processes involved with ccRCC by regulating the immune microenvironment.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/genética , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica/imunologia , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Neoplasias Renais/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/cirurgia , Linhagem Celular Tumoral , Biologia Computacional , Proteínas de Ligação a DNA/análise , Feminino , Fatores de Troca do Nucleotídeo Guanina/análise , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Rim/patologia , Rim/cirurgia , Neoplasias Renais/imunologia , Neoplasias Renais/mortalidade , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Nefrectomia , Prognóstico , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Regulação para Cima/imunologia , Adulto JovemRESUMO
PURPOSE: The mitogen-activated protein kinases (MAPKs) and protein kinase B (AKT) pathways have emerged as essential intracellular signaling pathways in eukaryotic cells, particularly as regulators of cardiac hypertrophy. Previous studies indicated that arctiin, an active ingredient of biennial dried ripe burdock, could exhibit potent anti-inflammatory and anti-allergic activities via down-regulating the activation of MAPKs and AKT pathways. However, little is known about its effects on cardiac hypertrophy. Therefore, the present study aimed to explore whether arctiin could attenuate cardiac hypertrophy. GENERAL METHODS: Arctiin (80 mg/kg) was administered by oral gavage once daily for 3 weeks from 1 week after surgery. Then, the mice were subjected to either chronic pressure overload generated by aortic banding (AB) or sham surgery (control group). Cardiac function was assessed by echocardiography. FINDINGS: The results indicated that arctiin attenuated cardiac hypertrophy induced by AB, and suppressed cardiac fibrosis and accumulation of collagen in vivo. Arctiin also inhibit the activation of MAPKs and AKT occurs in response to hypertrophic stimuli. Arctiin attenuated phenylephrine-induced hypertrophy of myocytes in vitro. CONCLUSIONS: In conclusion, arctiin can improve cardiac function and prevent the development of cardiac hypertrophy by blocking the MAPKs and AKT signaling pathways.
Assuntos
Cardiomegalia/tratamento farmacológico , Cardiomegalia/etiologia , Furanos/farmacologia , Furanos/uso terapêutico , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fitoterapia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Administração Oral , Animais , Arctium/química , Cardiomegalia/patologia , Células Cultivadas , Modelos Animais de Doenças , Fibrose , Furanos/administração & dosagem , Glucosídeos/administração & dosagem , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/patologiaRESUMO
AIMS/HYPOTHESIS: Oxidative stress, inflammation and cell death are closely involved in the development of diabetic cardiomyopathy (DCM). C1q/tumour necrosis factor-related protein-3 (CTRP3) has anti-inflammatory properties but its role in DCM remains largely unknown. The aims of this study were to determine whether CTRP3 could attenuate DCM and to clarify the underlying mechanisms. METHODS: Streptozotocin (STZ) was injected intraperitoneally to induce diabetes in Sprague-Dawley rats. Cardiomyocyte-specific CTRP3 overexpression was achieved using an adeno-associated virus system 12 weeks after STZ injection. RESULTS: CTRP3 expression was significantly decreased in diabetic rat hearts. Knockdown of CTRP3 in cardiomyocytes at baseline resulted in increased oxidative injury, inflammation and apoptosis in vitro. Cardiomyocyte-specific overexpression of CTRP3 decreased oxidative stress and inflammation, attenuated myocyte death and improved cardiac function in rats treated with STZ. CTRP3 significantly activated AMP-activated protein kinase α (AMPKα) and Akt (protein kinase B) in H9c2 cells. CTRP3 protected against high-glucose-induced oxidative stress, inflammation and apoptosis in vitro. AMPKα deficiency abolished the protective effects of CTRP3 in vitro and in vivo. Furthermore, we found that CTRP3 activated AMPKα via the cAMP-exchange protein directly activated by cAMP (EPAC)-mitogen-activated protein kinase kinase (MEK) pathway. CONCLUSIONS/INTERPRETATION: CTRP3 protected against DCM via activation of the AMPKα pathway. CTRP3 has therapeutic potential for the treatment of DCM.